Androgen receptor modulating compounds

ABSTRACT

The present disclosure relates to compounds of formula (I), and pharmaceutically acceptable salts thereof. The present disclosure also relates to compositions and methods of treating comprising compounds of formula (I), and pharmaceutically acceptable salts thereof.

This is a continuation of pending application Ser. No. 14/598,973, filedJan. 16, 2015, which is a continuation of prior application Ser. No.13/504,511, filed Apr. 27, 2012, and issued Mar. 10, 2015, as U.S. Pat.No. 8,975,254, which is a national stage filing under 35 U.S.C. §371 ofInternational Application No. PCT/FI2010/000065, filed Oct. 27, 2010,which claims the benefit of priority to U.S. Provisional Application No.61/255,159, filed Oct. 27, 2009, all of which are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to therapeutically active compounds andpharmaceutically acceptable salts and esters thereof useful in thetreatment of nuclear receptor, especially steroid receptor, and inparticular androgen receptor (AR) dependent conditions and diseases, andto pharmaceutical compositions containing such compounds. In particular,the invention discloses non-steroidal carboxamide and acyl hydrazonestructured compounds having utility as tissue-selective androgenreceptor modulators (SARM). The compounds of the invention, whichpossess AR antagonist activity, are useful for treating patientsrequiring androgen receptor antagonist therapy. In particular, ARantagonists of the invention are useful in the treatment or preventionof cancer, particularly AR dependent cancer such as prostate cancer, andother diseases where AR antagonism is desired.

BACKGROUND OF THE INVENTION

In recent years, there has been growing interest in the development ofnonsteroidal modulators for steroid receptors for therapeutical use. Ithas been shown that nonsteroidal ligands can achieve better receptorselectivity and better physicochemical, pharmacokinetic andpharmacological properties. For androgen receptor (AR), nonsteroidalantagonists (antiandrogens) are now used clinically to counteract theundesirable actions of excessive androgens.

Androgens, functioning through the AR, are essential for the initiationand progression of prostate cancer. Thus, treatment of advanced prostatecancer involves androgen-ablation therapies, such as surgical castrationor hormonal manipulation using gonadotropin-releasing hormone (GnRH)agonists, anti-androgens or both. Although such therapies initially leadto disease regression, eventually all patients progress to a castrationresistant late stage that is refractory to current therapies.Castration-resistant prostate cancer (CRPC) is associated with increasedlevels of AR. First generation anti-androgens such as bicalutamidedisplay agonistic properties in cells engineered to express higher ARlevels. In vitro and in vivo, increased AR expression has been shown toconfer resistance of prostate cancer cell lines to anti-androgentherapy. To overcome resistance problems, second generationanti-androgens that retain antagonism in cells expressing excess AR mayhave utility in the treatment of CRPC.

Non-steroidal androgen receptor antagonists have been described earliere.g. in patent publications EP 100172, EP 1790640, U.S. Pat. No.6,087,509, U.S. Pat. No. 6,673,799, U.S. Pat. No. 7,271,188, WO03/057669, WO 2004/099188, WO 2006/133567, WO 2008/124000, WO2009/028543 and WO 2009/055053.

Related carboxamide structured compounds have been described in WO2008/062878.

SUMMARY OF THE INVENTION

It has been found that compounds of formula (I) or (I′) are potentandrogen receptor (AR) modulators, in particular AR antagonists.Compounds of formula (I) or (I′) show remarkably high affinity andstrong antagonistic activity in androgen receptor. Also in cells whichoverexpress AR (“AR overexpressing cells”) the compounds of theinvention possess from high to full AR antagonism while exhibiting onlyminimal agonism. The compounds of the invention also effectivelyinhibited proliferation of prostatic cancer cell line. Moreover, thecompounds of the invention have low potential for drug-druginteractions, favourable safety profile and sufficient water solubility.

The compounds of the invention are therefore particularly useful asmedicaments in the treatment of prostate cancer and other AR dependentconditions and diseases where AR antagonism is desired.

The present invention provides novel carboxamide structured compounds offormula (I)

wherein

R₁ is hydrogen, halogen, cyano, nitro or optionally substituted 5- or6-membered heterocyclic ring;

R₂ is hydrogen, halogen, cyano, nitro, amino, C₁₋₇ alkyl, halo C₁₋₇alkyl, hydroxy C₁₋₇ alkyl, thio C₁₋₇ alkyl or C₁₋₇ alkoxy;

R₃ is hydrogen, halogen or C₁₋₇ alkyl,

or R₂ and R₃ together with the carbon atoms to which they are attachedform a optionally substituted 5- or 6-membered carbocyclic orheterocyclic ring;

wherein at least two of R₁, R₂ and R₃ are not hydrogen;

R₄, R₄′, R₅, R₆ and R₇ are, independently, hydrogen, C₁₋₇ alkyl, haloC₁₋₇ alkyl or hydroxy C₁₋₇ alkyl;

ring atom E is C or N;

dashed line means an optional double bond;

A is a 5-12 membered heterocyclic ring;

B is a 5-membered heterocyclic ring wherein I-3 of the members areheteroatoms selected from N, O and S;

R₈ is hydrogen, hydroxy, halogen, nitro, amino, cyano, oxo, C₁₋₇ alkyl,C₁₋₇ alkoxy, halo C₁₋₇ alkyl, hydroxy C₁₋₇ alkyl, cyano C₁₋₇ alkyl,amino C₁₋₇ alkyl, oxo C₁₋₇ alkyl, C₁₋₇ alkoxy C₁₋₇ alkyl,methylsulfonamido C₁₋₇ alkyl, oxiran C₁₋₇ alkyl, C₁₋₇ alkylamino,hydroxy C₁₋₇ alkylamino, C₁₋₇ alkoxy C₁₋₇ alkylamino, C₁₋₇ alkylaminoC₁₋₇ alkyl, hydroxy C₁₋₇ alkylamino C₁₋₇ alkyl, hydroxyimino C₁₋₇ alkyl,halo C₁₋₇ alkylhydroxy C₁₋₇ alkyl, —C(O)R₁₀, —OC(O)R₁₇, —NH—C(O)R₁₈ oran optionally substituted 5-12 membered carbocyclic or heterocyclicring, each group optionally linked to A-ring via C₁₋₇ alkylene linker;

R₉ is hydrogen, halogen, C₁₋₇ alkyl, oxo, hydroxy C₁₋₇ alkyl, oxo C₁₋₇alkyl or an optionally substituted 5 or 6 membered carbocyclic orheterocyclic ring, each group optionally linked to A-ring via C₁₋₇alkylene linker;

R₁₀ is hydrogen, hydroxy, C₁₋₇ alkyl, hydroxy C₁₋₇ alkyl, halo C₁₋₇alkyl, C₁₋₇ alkoxy, NR₁₁R₁₂, or an optionally substituted 5-12 memberedcarbocyclic or heterocyclic ring;

R₁₁ is hydrogen, C₁₋₇ alkyl, hydroxy C₁₋₇ alkyl, amino C₁₋₇ alkyl, C₁₋₇alkyl amino C₁₋₇ alkyl,

R₁₂ is hydrogen or C₁₋₇ alkyl;

R₁₃ and R₁₄ are, independently, hydrogen, C₁₋₇ alkyl, halogen, cyano orhydroxy C₁₋₇ alkyl;

R₁₅ and R₁₆ are, independently, hydrogen, oxo, thioxo, C₁₋₇ alkyl orcyano;

R₁₇ is C₁₋₇ alkyl, C₁₋₇ alkoxy, amino C₁₋₇ alkyl or C₁₋₇ alkylamino C₁₋₇alkyl;

R₁₈ is C₁₋₇ alkyl, amino C₁₋₇ alkyl or C₁₋₇ alkylamino C₁₋₇ alkyl;

and pharmaceutically acceptable salts thereof.

In one class of preferred compounds of formula (I) are compounds whereinB is a group of formula (1′) the substituents of B being R₁₃ and R₁₄

wherein Z is O, N, C═O or C═S; X is C or N; Y is C or N; G is CH, C═O orC═S and M is CH or O; a dashed line means an optional double bond, theasterisk denotes the point of attachment to the ring, and R₁₃ and R₁₄are as defined above for compounds of formula (I).

In another class of preferred compounds of formula (I) are compoundswherein B is a group of formula (2′), (3′) or (4′) the substituents of Bbeing R₁₃ and R₁₄ which are again as defined above for compounds offormula (I), and the asterisk denotes the point of attachment to thering.

In another class of preferred compounds of formula (I) are compounds offormula (II), wherein R₁, R₂, R₃, R₄, R₄′, R₅, R₆, R₇, R₈, R₉ R₁₃, R₁₄,A, E, Z, X, Y, G and M are as defined above for compounds of formula

In one class of preferred compounds of formula (I) are compounds offormula (III), wherein R₁, R₂, R₃, R₄, R₄′, R₅, R₆, R₇, R₈, R₉ R₁₃, R₁₄,A and E are as defined above for compounds of formula (I).

In other class of preferred compounds of formula (I) are compounds offormula (IV), wherein R₁, R₂, R₃, R₄, R₄′, R₅, R₆, R₇, R₈, R₉ R₁₃, R₁₄,A and E are as defined above for compounds of formula (I).

In other class of preferred compounds of formula (I) are compounds offormula (V), wherein R₁, R₂, R₃, R₄, R₄′, R₅, R₆, R₇, R₈, R₉ R₁₃, R₁₄, Aand E are as defined above for compounds of formula (I).

In other class of preferred compounds of formula (I) are compounds offormula (VI), wherein R₁ is halogen, methyl, cyano, nitro ortrifluoromethyl; R₂ is cyano, halogen or nitro; R₃ is hydrogen, halogenor methyl; R₄ is hydrogen or methyl; R₅ is hydrogen or C₁₋₃ alkyl; A,R₈, and R₉ are as defined above for compounds of formula (I).

One preferred subclass of compounds of formula (VI) are compounds,wherein R₁ is halogen, R₂ is cyano; R₃ is hydrogen, halogen or methyl;R₄ is hydrogen, R₅ is methyl, and A, R₈, and R₉ are as defined above forcompounds of formula (I).

On the other aspect, the present invention provides the use ofcarboxamide structured and acyl hydrazone structured compounds offormula (I′)

wherein

R₁ is hydrogen, halogen, cyano, nitro or optionally substituted 5- or6-membered heterocyclic ring;

R₂ is hydrogen, halogen, cyano, nitro, amino, C₁₋₇ alkyl, halo C₁₋₇alkyl, hydroxy C₁₋₇ alkyl, thio C₁₋₇ alkyl or C₁₋₇ alkoxy;

R₃ is hydrogen, halogen or C₁₋₇ alkyl,

or R₂ and R₃ together with the carbon atoms to which they are attachedform a optionally substituted 5- or 6-membered carbocyclic orheterocyclic ring;

wherein at least two of R₁, R₂ and R₃ are not hydrogen;

R₄, R₄′, R₅, R₆ and R₇ are, independently, hydrogen, C₁₋₇ alkyl, haloC₁₋₇ alkyl or hydroxy C₁₋₇ alkyl;

ring atom E is C or N;

D is C or N;

dashed line means an optional double bond;

A is a 5-12 membered heterocyclic ring;

B is a 5-membered heterocyclic ring wherein 1-3 of the members areheteroatoms selected from N, O and S;

R₈ is hydrogen, hydroxy, halogen, nitro, amino, cyano, oxo, C₁₋₇ alkyl,C₁₋₇ alkoxy, halo C₁₋₇ alkyl, hydroxy C₁₋₇ alkyl, cyano C₁₋₇ alkyl,amino C₁₋₇ alkyl, C₁₋₇ alkoxy C₁₋₇ alkyl, methylsulfonamido C₁₋₇ alkyl,oxiran C₁₋₇ alkyl, C₁₋₇ alkylamino, hydroxy C₁₋₇ alkylamino, C₁₋₇ alkoxyC₁₋₇ alkylamino, C₁₋₇ alkylamino C₁₋₇ alkyl, hydroxy C₁₋₇ alkylaminoC₁₋₇ alkyl, hydroxyimino C₁₋₇ alkyl, halo C₁₋₇ alkylhydroxy C₁₋₇ alkyl,—C(O)R₁₀, —OC(O)R₁₇, —NH—C(O)R₁₈ or an optionally substituted 5-12membered carbocyclic or heterocyclic ring, each group optionally linkedto A-ring via C₁₋₇ alkylene linker;

R₉ is hydrogen, halogen, C₁₋₇ alkyl, oxo, or an optionally substituted 5or 6 membered carbocyclic or heterocyclic ring, each group optionallylinked to A-ring via C₁₋₇ alkylene linker;

R₁₀ is hydrogen, hydroxy, C₁₋₇ alkyl, hydroxy C₁₋₇ alkyl, halo C₁₋₇alkyl, C₁₋₇ alkoxy, NR₁₁R₁₂, or an optionally substituted 5-12 memberedcarbocyclic or heterocyclic ring;

R₁₁ is hydrogen, C₁₋₇ alkyl, hydroxy C₁₋₇ alkyl, amino C₁₋₇ alkyl, C₁₋₇alkyl amino C₁₋₇ alkyl,

R₁₂ is hydrogen or C₁₋₇ alkyl;

R₁₃ and R₁₄ are, independently, hydrogen, C₁₋₇ alkyl, halogen, cyano,halogen C₁₋₇ alkyl or hydroxy C₁₋₇ alkyl;

R₁₅ and R₁₆ are, independently, hydrogen, oxo, thioxo, C₁₋₇ alkyl orcyano;

R₁₇ is C₁₋₇ alkyl, C₁₋₇ alkoxy, amino C₁₋₇ alkyl or C₁₋₇ alkylamino C₁₋₇alkyl;

R₁₈ is C₁₋₇ alkyl, amino C₁₋₇ alkyl or C₁₋₇ alkylamino C₁₋₇ alkyl;

and pharmaceutically acceptable salts thereof;

in the manufacture of a medicament for the prevention or treatment ofandrogen receptor (AR) dependent disorders.

In one class of preferred compounds of formula (I′) are compounds offormula (II′), wherein R₁, R₂, R₃, R₄, R₄′, R₅, R₆, R₇, R₈, R₉ R₁₃, R₁₄,A, E, D, Z, X, Y, G and M are as defined above for compounds of formula(I′)

One particular class of compounds of formula (I′) are acyl hydrazonecompounds of formula (III′), wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉ R₁₃,R₁₄, R₁₅, R₁₆, A, B and E are as defined above as defined above forcompounds of formula (I′).

Another particular class of compounds of formula (I′) are acyl hydrazonecompounds of formula (IV′), wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉ R₁₃, R₁₄,R₁₅, R₁₆, A, E, Z, X, Y, G and M are as defined above for compounds offormula (I′)

Another particular class of compounds of formula (I′) or (III′) are acylhydrazone compounds wherein B is a group of formula (2′), (3′) or (4′)as defined above.

In another class of preferred compounds are compounds of formula (I),(II), (III), (IV), (V), (VI), (I′), (II′), (III′) or (IV′) wherein A isany one of the following groups or tautomers thereof:

wherein each of the above rings are substituted by R₈ and R₉ as definedabove. Preferred are compounds of formula (I), (II), (III), (IV), (V),(VI), (I′), (II′), (III′) or (IV′) wherein A is any one of groups (5′),(6′), (7′), (8′), (12′), (20′), (21′), (27′) and (28′) or tautomersthereof. One subclass of above preferred compounds is a class ofcompounds wherein R₈ is hydrogen, C₁₋₇ alkyl, hydroxy C₁₋₇ alkyl,halogen, pyridinyl, pyrazolyl, imidazolyl, furanyl, —C(O)R₁₀ or—OC(O)R₁₇, wherein R₁₀ is C₁₋₇ alkyl, R₁₇ is C₁₋₇ alkyl, and R₉ ishydrogen, halogen or C₁₋₇ alkyl, and wherein pyridinyl, pyrazolyl,imidazolyl, furanyl, —C(O)R₁₀, or —OC(O)R₁₇ groups may be linked toA-ring via C₁₋₇ alkylene linker. Preferred compounds of the abovesubclass are compounds wherein R₁ is halogen, R₂ is cyano; R₃ ishydrogen, halogen or methyl; R₄ is hydrogen, and R₅ is methyl.

Still another class of preferred compounds are compounds of formula (I),(I′) or (III′) wherein

ring atom E is C,

R₁ is halogen, C₁₋₇ alkyl, cyano, nitro or halo C₁₋₇ alkyl,

R₂ is cyano, halogen or nitro,

R₃ is hydrogen, halogen or C₁₋₇ alkyl,

A is any one of groups (5′), (6′), (7′), (8′), (12′), (20′), (21′),(27′) and (28′) or tautomers thereof,

B is a group of formula (2′), (3′) or (4′) substituted by R₁₃ and R₁₄,which are hydrogen,

R₄ (and R₄′ if applicable) is hydrogen or methyl,

R₅ is hydrogen or C₁₋₇ alkyl,

R₆ (if applicable) is hydrogen,

R₈ is hydrogen, C₁₋₇ alkyl, hydroxy C₁₋₇ alkyl, halogen, hydroxyiminoC₁₋₇ alkyl, a 5 or 6 membered heterocyclic ring or —C(O)R₁₀ wherein R₁₀is C₁₋₇ alkyl, and

R₉ is hydrogen, halogen or C₁₋₇ alkyl.

The present invention provides further a method for the treatment orprevention of androgen receptor (AR) dependent conditions, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of formula (I) or (I′). For example, the ARdependent condition to be treated is cancer, particularly AR dependentcancer such as prostate cancer, benign prostatic hyperplasia, androgenicalopecia and acne. According to one embodiment of the invention, the ARdependent condition to be treated is castration-resistant prostatecancer (CRPC).

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) together with a pharmaceuticallyacceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention can be prepared by a variety of syntheticroutes analogously to the methods known in the literature using suitablestarting materials. For example, compounds of formula (I) wherein R₄,R₄′, R₆, and R₇ are hydrogen, and R₁, R₂, R₃, R₅, R₈, R₉ R₁₃, R₁₄, R₁₅,R₁₆, A, B and E are as defined above for compounds of formula (I) can beprepared e.g. analogously or according to the reaction Scheme 1. Somecompounds included in the formula (I) can be obtained by converting thefunctional groups of the other compounds of formula (I) obtained inaccordance with Scheme 1, by well known reaction steps such asoxidation, reduction, hydrolysis, acylation, alkylation, amidation,amination and others.

Compounds of formula (I) wherein R₈ is —C(O)R₁₀ and R₁₀ is NR₁₁R₁₂ or anoptionally substituted 5-12 membered heterocyclic ring attached tocarbonyl carbon via the ring atom N can be suitably prepared accordingto the Scheme 2 (said heterocyclic ring illustrated as “C”). R₁, R₂, R₃,R₅, R₉ R₁₃, R₁₄, R₁₅, R₁₆, A, B and E are again as defined above forcompounds of formula (I).

Compounds of formula (I) wherein B is a pyrazole ring (3′) can besuitably prepared from the intermediate compound of formula (16) usingthe methods of Scheme 1 or 2. The intermediate compound of formula (16)can be suitably prepared according to Scheme 3, wherein R₁, R₂, R₃, R₅,R₆ and E are as defined above for compounds of formula (I).

Optically active enantiomers or diastereomers of compounds of formula(I) can be prepared e.g. by using suitable optically active startingmaterials. For example, optically active enantiomers of compounds offormula (I) can be prepared from optically active intermediate compoundsof formula (16a) using the methods of Scheme 1 or 2. The opticallyactive intermediate compound of formula (16a) can be suitably preparedaccording to Scheme 4 or Scheme 5, wherein R₁, R₂, R₃, R₄, R′₄, R₅, R₆and E are as defined above for compounds of formula (I).

Alternatively, the intermediate compound of formula (16) can be preparedaccording to Scheme 6, wherein R₁, R₂, R₃, R₄, R′₄, R₅, R₆ and E are asdefined above for compounds of formula (I) and Tr is a trityl (triphenylmethyl) group.

Compounds of formula (I) having the optional double bond can be suitablyprepared according to Scheme 7, wherein R₁, R₂, R₃, R₅, R₈, R₉, R₁₃,R₁₄, R₁₅, R₁₆, A, B and E are as defined above for compounds of formula(I).

Acyl hydrazone compounds of formula (I′), wherein D is N, arecommercially available or can be prepared, for example, according toScheme 8, wherein R₁, R₂, R₃, R₄, R₈, R₉, R₁₃, R₁₄, R₁₅, R₁₆, A, B and Eare as defined above for compounds of formula (I′). Some compoundsincluded in the formula (I′) can be obtained by converting thefunctional groups of the other compounds of formula (I′) obtained inaccordance with Scheme 8, by well known reaction steps such asoxidation, reduction, hydrolysis, acylation, alkylation, amidation,amination and others.

The starting materials of the above Schemes are commercially availableor can be prepared according to known methods.

Pharmaceutically acceptable salts, e.g. acid addition salts with bothorganic and inorganic acids are well known in the field ofpharmaceuticals. Non-limiting examples of these salts include chlorides,bromides, sulfates, nitrates, phosphates, sulfonates, formates,tartrates, maleates, citrates, benzoates, salicylates and ascorbates.Pharmaceutically acceptable esters, when applicable, may be prepared byknown methods using pharmaceutically acceptable acids that areconventional in the field of pharmaceuticals and that retain thepharmacological properties of the free form. Non-limiting examples ofthese esters include esters of aliphatic or aromatic alcohols, e.g.methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butylesters. Phosphate esters and carbonate esters, are also within the scopeof the invention.

The definition of formula (I) above is inclusive of all the possibleisotopes and stereoisomers of the compounds, including geometricisomers, e.g. Z and E isomers (cis and trans isomers), and opticalisomers, e.g. diastereomers and enantiomers, and all prodrug esters,e.g. phosphate esters and carbonate esters. Furthermore, the inventionincludes in its scope both the individual isomers and any mixturesthereof, e.g. racemic mixtures.

In one embodiment, the term “isomer” is meant to encompass opticalisomers of the compounds of the invention. It will be appreciated bythose skilled in the art that the compounds of the present inventioncontain at least one chiral center. Accordingly, the compounds of theinvention may exist in optically active or racemic forms. It is to beunderstood that the present invention encompasses any racemic oroptically active form, or mixtures thereof. In one embodiment, thecompounds of the invention are the pure (R)-isomers. In anotherembodiment, the compounds of the invention are the pure (S)-isomers. Inanother embodiment, the compounds of the invention are a mixture of the(R) and the (S) isomers. In another embodiment, the compounds of theinvention are a racemic mixture comprising an equal amount of the (R)and the (S) isomers. The compounds of the invention may contain twochiral centers. In such case, according to one embodiment of theinvention, the compounds of the invention are pure diasteromers.According to other embodiment of the invention, the compounds of theinvention are a mixture of several diasteromers. The individual isomersmay be obtained using the corresponding isomeric forms of the startingmaterial or they may be separated after the preparation of the endcompound according to conventional separation methods. For theseparation of optical isomers, e.g. enantiomers or diastereomers, fromthe mixture thereof the conventional resolution methods, e.g. fractionalcrystallisation, may be used.

The terms employed herein have the following meanings:

The term “halo” or “halogen”, as employed herein as such or as part ofanother group, refers to chlorine, bromine, fluorine or iodine.

The term “C₁₋₇ alkyl”, as employed herein as such or as part of anothergroup, refers to a saturated or unsaturated straight, branched orcyclized chain radical having 1 to 7 carbon atoms. Representativeexamples of C₁₋₇ alkyl include, but are not limited to, methyl, ethyl,ethenyl, n-propyl, isopropyl, propenyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopentyl,cyclohexyl and the like.

The term “C₁₋₇ alkylene linker” means a saturated or unsaturatedstraight, branched or cyclized C₁₋₇ alkyl chain which connects twogroups together. Examples of C₁₋₇ alkylene linker are methylene (—CH₂—)and ethylene (—CH₂—CH₂—) chains.

The term “hydroxy”, as employed herein as such or as part of anothergroup, refers to an —OH group.

The term “cyano”, as employed herein as such or as part of anothergroup, refers to a —CN group.

The term “hydroxy C₁₋₇ alkyl”, as employed herein, refers to at leastone hydroxy group, as defined herein, appended to the parent molecularmoiety through an C₁₋₇ alkyl group, as defined herein. Representativeexamples of hydroxy C₁₋₇ alkyl include, but are not limited to,hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,1-hydroxypropyl, 1-methyl-1-hydroxyethyl, 1-methyl-1-hydroxypropyl, andthe like.

The term “halo C₁₋₇ alkyl”, as employed herein, refers to at least onehalogen, as defined herein, appended to the parent molecular moietythrough a C₁₋₇ alkyl group, as defined herein. Representative examplesof halo C₁₋₇ alkyl include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl, and thelike.

The term “C₁₋₇ alkoxy”, as employed herein as such or as part of anothergroup, refers to —O—C₁₋₇ alkyl wherein C₁₋₇ alkyl is as defined herein.Representative examples of C₁₋₇ alkoxy include, but are not limited tomethoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,and the like.

The term “thio C₁₋₇ alkyl”, as employed herein, refers to —S—C₁₋₇ alkyl,wherein C₁₋₇ alkyl is as defined herein. Representative examples of thioC₁₋₇ alkyl include, but are not limited to thiomethyl (—SCH₃),thioethyl, and the like.

The term “oxo” means a double-bonded group (═O) attached as asubstituent.

The term “thioxo” means a double-bonded group (═S) attached as asubstituent.

The term “amino”, as employed herein as such or as part of anothergroup, refers to a —NH₂ group.

The term “C₁₋₇ acyl” as employed herein by itself or as part of anothergroup refers to C₁₋₇ alkylcarbonyl group, and examples thereof includeacetyl, propanoyl, isopropanoyl, butanoyl, sec-butanoyl, tert-butanoyland pentanoyl.

The term “amino C₁₋₇ alkyl”, as employed herein, refers to at least oneamino group, as defined herein, appended to the parent molecular moietythrough an C₁₋₇ alkyl group, as defined herein. Representative examplesof amino C₁₋₇ alkyl include, but are not limited to, aminomethyl,2-aminoethyl, 1-aminoethyl, 2,2-diaminoethyl, 3-aminopropyl,2-aminopropyl, 4-aminobutyl, 1-methyl-1-aminoethyl, and the like.

The term “C₁₋₇ alkylamino”, as employed herein as such or as part ofanother group, refers to one or two C₁₋₇ alkyl group(s), as definedherein, appended to the parent molecular moiety through an amino group,as defined herein. Representative examples of C₁₋₇ alkylamino include,but are not limited to methylamino, ethylamino, propylamino, butylamino,dimethylamino, diethylamino, N-ethyl-N-methylamino, and the like.

The term “C₁₋₇ alkylamino C₁₋₇ alkyl”, as employed herein, refers toC₁₋₇ alkylamino group, as defined herein, appended to the parentmolecular moiety through a C₁₋₇ alkyl group, as defined herein.Representative examples of C₁₋₇ alkylamino C₁₋₇ alkyl include, but arenot limited to, N,N-dimethylaminomethyl, N,N-diethylaminomethyl,N-methylaminoethyl, N-methylaminopropyl, N-ethyl-N-methylaminomethyl,and the like.

The term “hydroxy C₁₋₇ alkylamino C₁₋₇ alkyl”, as employed herein,refers to hydroxy C₁₋₇ alkylamino group, as defined herein, appended tothe parent molecular moiety through a C₁₋₇ alkyl group, as definedherein. Representative examples of C₁₋₇ alkylamino C₁₋₇ alkyl include,but are not limited to, N-hydroxymethylaminoethyl,N-ethyl-N-hydroxymethylaminomethyl, and the like.

The term “C₁₋₇ alkoxy C₁₋₇ alkyl”, as employed herein, refers to atleast one C₁₋₇ alkoxy group, as defined herein, appended to the parentmolecular moiety through a C₁₋₇ alkyl group, as defined herein.Representative examples of C₁₋₇ alkoxy C₁₋₇ alkyl include, but are notlimited to methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl,3,3-dimethoxypropyl, 2,4-dimethoxybutyl and the like.

The term “imino C₁₋₇ alkyl”, as employed herein, refers to at least oneimino group (═NH) appended to the parent molecular moiety through a C₁₋₇alkyl group, as defined herein.

The term “hydroxyimino C₁₋₇ alkyl”, as employed herein, refers to ═N—OHgroup appended to the parent molecular moiety through a C₁₋₇ alkylgroup, as defined herein.

The term “5- or 6-membered heterocyclic ring” as employed herein, refersto a saturated, partially saturated or aromatic ring with 5 or 6 ringatoms, of which 1-3 atoms are heteroatoms selected from a groupconsisting of N, O and S. Representative examples of 5- or 6-memberedheterocyclic ring include, but are not limited to, pyrazolyl, furanyl,piperazinyl, piperidinyl, pyridinyl rings and the like.

The term “5- or 6-membered carbocyclic ring” as employed herein, refersto a saturated, partially saturated or aromatic ring with 5 or 6 ringatoms consisting of carbon atoms only. Representative examples of 5- or6-membered carbocyclic ring include, but are not limited to, phenyl andcyclohexyl rings and the like.

The term “5-12 membered heterocyclic ring” as employed herein, refers toa monocyclic or bicyclic saturated, partially saturated or aromatic ringwith 5 to 12 ring atoms, of which 1-4 atoms are heteroatoms selectedfrom a group consisting of N, O and S. Representative examples of 5-12membered heterocyclic ring include, but are not limited to, pyrazolyl,furanyl, piperazinyl, piperidinyl, pyridinyl, morpholinyl, pyrazinyl,indazolyl, imidazolyl, pyrazolo[1,5-a]pyrimidinyl, isoxazolyl andthiazolyl rings and the like.

The term “5-12 membered carbocyclic ring” as employed herein, refers toa saturated, partially saturated or aromatic ring with 5 to 12 ringatoms consisting of carbon atoms only. Representative examples of 5-12membered carbocyclic ring include, but are not limited to, phenyl,naphtyl and cyclohexyl rings and the like.

The term “optionally substituted” as used herein in connection withvarious residues refers to halogen substituents, such as fluorine,chlorine, bromine, iodine, or C₁₋₇ alkyl, hydroxy, amino, halo C₁₋₇alkyl, hydroxy C₁₋₇ alkyl, C₁₋₇ alkoxy, C₁-C₇ acyl, C₁₋₇ alkylamino,amino C₁₋₇ alkyl, methylsulfonyl, nitro, cyano, thiol, or 5- or6-membered carbocyclic or heterocyclic ring substituents. Preferredsubstituents are halogen, C₁₋₇ alkyl, hydroxy C₁₋₇ alkyl, C₁-C₇ acyl,pyridinyl, morpholinyl and benzyl substituents.

The “optionally substituted” groups may contain 1 to 3, preferably 1 or2, most preferably 1 of the above mentioned substituents.

Examples of preferred compounds of formula (I) include

-   N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-(morpholine-4-carbonyl)-1H-pyrazole-5-carboxamide;-   (S/R)—N-(1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-yl)-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide;-   (S)—N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide;-   (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide;-   N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide;-   N-(2-(3-(3,4-dicyanophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide;-   (R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide;-   N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide;-   (S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide;-   (R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamide;-   (R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide;-   N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide;-   3-tert-butyl-N-(1-(5-(4-cyano-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-yl)-1H-pyrazole-5-carboxamide;-   3-tert-butyl-N-(2-(5-(3-chloro-4-cyano-2-methylphenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide;-   N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamide;-   (S)-5-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide;-   (R)—N-(1-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide;-   (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide;-   N—((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyano-2-methyl    phenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methylisoxazole-3-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyano-2-methyl    phenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide;-   (R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamide;-   (R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-methylthiazol-4-yl)-1H-pyrazole-3-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-methyl-1,2,4-oxadiazole-5-carboxamide;-   (R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-morpholinothiazole-4-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide;-   N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)isoxazole-3-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-ethyl-1,2,4-oxadiazole-5-carboxamide;-   N—((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide;-   (R)—N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-2-(cyanomethyl)thiazole-4-carboxamide;-   (S)—N-{1-[3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)imidazo[1,2-a]pyrimidine-2-carboxamide;-   (S)-3-acetyl-N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide;-   (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide;

Compounds of the invention may be administered to a patient intherapeutically effective amounts which range usually from about 0.1 toabout 5000 mg, preferably from about 1 to about 2000 mg, per daydepending on the age, weight, ethnic group, condition of the patient,condition to be treated, administration route and the androgen (AR)modulator used. The compounds of the invention can be formulated intodosage forms using the principles known in the art. It can be given to apatient as such or in combination with suitable pharmaceuticalexcipients in the form of tablets, granules, capsules, suppositories,emulsions, suspensions or solutions. Choosing suitable ingredients forthe composition is a routine for those of ordinary skill in the art. Itis evident that suitable carriers, solvents, gel forming ingredients,dispersion forming ingredients, antioxidants, colours, sweeteners,wetting compounds and other ingredients normally used in this field oftechnology may be also used. The compositions containing the activecompound can be given enterally or parenterally, the oral route beingthe preferred way. The contents of the active compound in thecomposition is from about 0.5 to 100%, preferably from about 1 to about85%, per weight of the total composition.

The present invention will be explained in more detail by the followingexamples. The examples are meant only for illustrating purposes and donot limit the scope of the invention defined in claims.

Experiments

Experiment 1.

AR binding affinity (Ki) of the test compound was measured.

AR antagonism of the test compound was measured as IC₅₀ value (nM) tohuman AR in hAR/HEK293 cells.

AR agonism of the test compound in AR overexpressing hAR/HEK293 cellswas measured as % of testosterone-induced AR activity at 10 uMconcentration.

The IC₅₀ value of the test compound for inhibition of mibolerone-inducedVCaP cell proliferation was measured.

Bicalutamide was used as a reference compound in the measurements.

Methods

Androgen Receptor Binding Assay

Androgen receptor (AR) binding affinities of test compounds were studiedin cytosolic lysates obtained from ventral prostates of castrated ratsby competition binding assay (Schilling K. and Liao S., The Prostate,1984; 5(6):581-588). Cytosol preparations and 1 nM [3H]mibolerone wereincubated with increasing concentrations of test compounds. To determinenon-specific binding, parallel incubations were carried out using excessof unlabelled testosterone. After incubation, bound and free steroidswere separated by treatment with dextran-coated charcoal suspension.Bound radioactivity was determined by counting of supernatant fractionin scintillation fluid. Radioactivity was measured using a Microbetacounter. All data points were done as quadrublicates. Dissociationconstant of [3H]mibolerone for rat androgen receptor was determined bysaturation binding assay obtained from ventral prostates of castratedrats essentially as described (Isomaa V. et al., Endocrinology, 1982;111(3):833-843).

Analysis of Data

For analysis of saturation binding affinity, one site binding equation(hyperbola) was used

${{Specific}\mspace{14mu} {binding}} = \frac{B_{{ma}\; x}*X}{{Kd} + X}$

whereB_(max)=the maximum specific bindingKd=the equilibrium dissociation constantX=radioligand concentration

Equilibrium dissociation constant (Ki) was calculated using the equationof Cheng and Prusoff:

$K_{i} = \frac{{IC}\; 50}{1 + \frac{\lbrack{radioligand}\rbrack}{K_{d}}}$

where

[radioligand]=the concentration of free radioligand

K_(d)=the dissociation constant of the radioligand for the receptor

IC50=IC₅₀ value measured in a competition radioligand binding assay

AR Antagonism

Antagonism of test compounds for AR was measured by reporter gene assayin human embryonic kidney (HEK293) cells stably transfected with anexpression vector encoding full-length human AR and androgen responsiveluciferase reporter gene construct (hAR/HEK293 cells). To determineantagonism for hAR, the cells were treated simultaneously withincreasing concentrations of the test compound and submaximalconcentration of testosterone (usually 0.45 nM). The final DMSOconcentration was 1%. All test compounds were studied in triplicates.The cells were incubated for 24 before measurement of luciferaseactivity using Luciferase Assay System (Promega Corporation).

Agonism of test compounds in AR overexpressing cells was measured byreporter gene assay in HEK293 cells stably transfected with anexpression vector encoding full-length human AR and androgen responsiveluciferase reporter gene construct. A clone expressing high levels ofandrogen receptor (5 times more than AR levels in AR-HEK293 cells) wasselected to study agonism in AR overexpressing cells. To determineagonism, the cells were treated with increasing concentrations of thetest compound. The final DMSO concentration was 1%. The test compoundswere studied in triplicates and luciferase activity was determined asdescribed above.

Cell Proliferation Assays

The ability of test compounds to inhibit prostate cancer cell growth wasstudied by measuring inhibition of cell proliferation usingandrogen-sensitive VCaP prostate cancer cell line. Cells were seeded ata density of 50 000 cells/well in a 96-well plate in the appropriateculture medium (phenol red-free RPMI-1640 supplemented with 10% charcoalstripped FBS and 4 mM Glutamax+100 IU penicillin, 100 IU streptomycin).The cells were allowed to attach for 2-3 days and were subsequentlytreated with the test compounds in the presence of mibolerone (aconcentration capable of inducing submaximal increase in cellproliferation, usually 0.1 nM) for 4-5 days. Cell proliferation wasmeasured using WST-1 Cell Proliferation Assay (Roche).

TABLE 1 AR binding affinity, AR antagonism, AR agonism in ARoverexpressing cells and inhibition of VCaP cell proliferation ARInhibition of binding AR Agonism in AR VCaP cell Compound of affinityantagonism overexpressing proliferation Example No. Ki (nM) IC₅₀(nM)cells (%) IC₅₀ (nM) 8 62 606 0 1600 32 6 34 39 560 34 16 172 39 600 5227 149 40 450 56 14 96 27 400 53 18 88 24 500 91 13 54 18 330 94 8 57 18790 103 17 71 19 230 124 38 133 5 430 132 29 93 21 210 186 3 11 >20 310206 12 29 >20 490 219 40 146 0 1400 222 12 33 20 250 248 31 190 7 490249 16 42 34 320 324 25 128 16 1000 338 14 42 25 340 Bicalutamide 40 22870 2000-3000

EXAMPLES

The end products of the following Examples were prepared as a mixture ofdiastereomers unless otherwise indicated.

Example 1 5-(Piperazine-1-carbonyl)-2H-pyrazole-3-carboxylic Acid{2-[5-(3,4-dichloro-phenyl)furan-2-yl]ethyl}amide a)2-(3,4-Dichlorophenyl)-5-((E)-2-nitrovinyl)furan

A stirred solution of acetic acid (1.4 ml, 1.46 g, 24.3 mmol) inmethanol (3.5 ml) under nitrogen atmosphere at 0° C. was treateddropwise with n-propylamine (2.0 ml, 1.42 g, 24.0 mmol). The resultingn-propylammonium acetate solution was stirred at 0° C. for 5 min, thenadded dropwise to a stirred solution of 5-(3,4-di-chlorophenyl)furfural(10.04 g, 41.6 mmol) in nitromethane (6.8 ml, 7.61 g, 124.7 mmol) at 0°C. The resulting mixture was stirred at 0° C. for 30 min. Then thecooling bath was removed, and stirring was continued at RT. From time totime, 10 ml of THF was added five times. After stirring overnight THFwas evaporated and water was added. A solid was filtrated, washed withwater and heptane to afford 11.46 g of2-(3,4-dichlorophenyl)-5-((E)-2-nitrovinyl)furan. ¹H NMR (400 MHz,DMSO-d₆): 7.38 (1H, d), 7.43 (1H, d), 7.76 (1H, d), 7.95 (1H, dd), 8.03(1H, d), 8.19 (1H, d), 8.31 (1H, d)

b) 2-[5-(3,4-Dichlorophenyl)furan-2-yl]ethylamine Hydrochloride

2-(3,4-Dichlorophenyl)-5-((E)-2-nitrovinyl)furan (5.73 g, 20.2 mmol) wasdissolved into the mixture of dry methanol (90 ml) and dry ethyl acetate(70 ml). Then, 14.3 ml of 10 w-% HCl-methanol and 2.4 g of 10% palladiumon carbon were added. 2-(3,4-Dichlorophenyl)-5-((E)-2-nitrovinyl)furanwas hydrogenated at 3 atm at RT for about 4 h. The catalyst was removedby filtrating through Celite®. Removal of solvent under reduced pressuregave a raw product which was purified by flash chromatography on silicagel using CH₂Cl₂/MeOH (98:2-80:20) as a gradient eluent. ¹H NMR (400MHz, DMSO-d₆): 3.04 (2H, m), 3.14 (2H, m), 6.43 (1H, d), 7.07 (1H, d),7.67 (2H, s), 7.93 (1H, s), 8.19 (3H, broad s).

c)5-{2-[5-(3,4-Dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylicAcid

3,5-Pyrazoledicarboxylic acid monohydrate (8.02 g, 46.1 mmol) wasdissolved in the mixture of dry DMF (35 ml), dry DCM (35 ml) and DIPEA(7.9 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDCI, 3.37 g, 17.6 mmol), HOBt (2.28 g, 16.9 mmol), and DIPEA (3 ml,2.23 g, 17.3 mmol) were added at RT. The solution was mixed for 10 min.Then, 2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride (3.46g, 11.8 mmol) dissolved in the mixture of dry DCM (35 ml) and DIPEA (2.0ml, 1.48 g, 11.5 mmol) was dropped to the solution at RT. After stirringovernight water was added. The product was extracted into ethyl acetate.The organic phase was washed with water, dried and evaporated. The crudeproduct was purified by flash chromatography using DCM as an eluent. Theproduct was triturated in hot methanol. ¹H NMR (400 MHz, DMSO-d₆): 2.95(2H, t), 3.56 (2H, m), 6.33 (1H, d), 7.01 (1H, d), about 7.03 (1H, broads), 7.61 (1H, distorted dd), 7.63 (1H, distorted d), 7.83 (1H, d), about8.45 (1H, broad s), about 14.05 (1H, broad s).

d) 5-(Piperazine-1-carbonyl)-2H-pyrazole-3-carboxylic Acid{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

5-{2-[5-(3,4-Dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylicacid (0.30 g, 0.76 mmol) was dissolved in the mixture of dry DMF (3 ml)and dry DCM (3 ml). EDCI (0.22 g, 1.2 mmol), HOBt (0.16 g, 1.2 mmol),and DIPEA (0.2 ml, 0.15 g, 1.2 mmol) were added at RT. After stirringfor 15 min piperazine (0.10 g, 1.2 mmol) in dry DCM (2 ml) was droppedto the solution at RT. Then the solution was stirred overnight. Waterwas added and the product was extracted into ethyl acetate. The organicphase was washed with brine and water, dried and evaporated. The crudeproduct was purified by flash chromatography using CH₂Cl₂-MeOH as agradient eluent (95:5-50:50). Another purification was made also byflash chromatography using CH₂Cl₂-MeOH (9:1) as an eluent. ¹H NMR (400MHz, CDCl₃): 2.94 (4H, m), 3.01 (2H, t), 3.77 (2H, q), about 3.8 (4H,m), 6.20 (1H, d), 6.58 (1H, d), 7.02 (1H, s), 7.21 (1H, broad s), 7.40(1H, distorted d), 7.43 (1H, distorted dd), 7.75 (1H, d).

Example 25-[4-(2-Hydroxyethyl)piperidine-1-carbonyl]-2H-pyrazole-3-carboxylicAcid {2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

The title compound was prepared as in the previous Example starting from5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylicacid and 4-piperidine ethanol. The crude product was purified by flashchromatography using CH₂Cl₂-MeOH as a gradient eluent (100:0-95:5). ¹HNMR (400 MHz, CDCl₃): 1.27 (3H, m), 1.57 (2H, m), 1.85 (3H, m), 2.81(1H, m), 3.01 (2H, t), about 3.21 (1H, m), 3.76 (4H, m), about 4.41 (1H,m), about 4.67 (1H, m), 6.20 (1H, d), 6.59 (1H, d), 7.02 (1H, s), 7.29(1H, broad s), 7.40 (1H, distorted d), 7.43 (1H, distorted dd), 7.75(1H, d), 11.4 (1H, broad s).

Example 3 5-(4-Hydroxypiperidine-1-carbonyl)-2H-pyrazole-3-carboxylicAcid {2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

The title compound was prepared as in Example 1 starting from5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylicacid and 4-hydroxypiperidine. The crude product was purified by flashchromatography using CH₂Cl₂-MeOH (95:5) as an eluent. ¹H NMR (400 MHz,CDCl₃): 1.62 (1H, d), 1.65 (2H, m), 1.95 (2H, m), 3.00 (2H, t), about3.57 (2H, m), 3.77 (2H, q), about 4.1 (3H, m), 6.20 (1H, d), 6.58 (1H,d), 7.03 (1H, s), about 7.6 (1H, broad s), 7.40 (1H, distorted d), 7.43(1H, distorted dd), 7.74 (1H, d), 11.6 (1H, broad s).

Example 45-[4-(2-Hydroxyethyl)piperazine-1-carbonyl]-2H-pyrazole-3-carboxylicAcid {2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

The title compound was prepared as as in Example 1 starting from5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylicacid and 1-(2-hydroxyethyl)piperazine. The crude product was purified byflash chromatography using CH₂Cl₂-MeOH as a gradient eluent(100:0-90:10). ¹H NMR (400 MHz, DMSO-d₆): 2.40-2.44 (6H, m), 2.95 (2H,t), about 3.5-3.7 (6H, m), about 3.82 (2H, m), 4.41 (1H, t), 6.33 (1H,d), 7.01 (1H, d), about 7.05 (1H, broad s), 7.59 (1H, distorted dd),7.63 (1H, distorted d), 7.84 (1H, d), about 8.59 (1H, broad s), 13.9(1H, broad s).

Example 5 5-(4-Acetylpiperazine-1-carbonyl)-2H-pyrazole-3-carboxylicAcid {2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

The title compound was prepared as in Example 1 starting from5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylicacid and 1-acetylpiperazine. The crude product was triturated in CH₂Cl₂at room temperature to afford the product. ¹H NMR (400 MHz, CDCl₃): 2.15(3H, s), 3.01 (2H, t), 3.58 (2H, m), 3.72 (2H, m), 3.78 (2H, q), 3.84(4H, m), 6.21 (1H, d), 6.59 (1H, d), 7.04 (1H, s), about 7.28 (1H, broads), 7.41 (2H, m), 7.74 (1H, s), 11.35 (1H, broad s).

Example 65-(4-Morpholin-4-ylpiperidine-1-carbonyl)-2H-pyrazole-3-carboxylic Acid{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

The title compound was prepared as in Example 1 starting from5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylicacid and 4-morpholinopiperidine. The crude product was purified by flashchromatography using CH₂Cl₂-MeOH as a gradient eluent (100:0-96:4). ¹HNMR (400 MHz, DMSO-d₆): about 1.32 (2H, m), about 1.82 (2H, m),2.45-2.47 (5H, m), about 2.78 (1H, m), 2.95 (2H, t), about 3.11 (1H, m),3.55-3.57 (6H, m), about 4.45 (1H, m), 6.34 (1H, d), 7.02 (1H, d), about7.03 (1H, broad s), 7.59 (1H, distorted dd), 7.63 (1H, distorted d),7.84 (1H, d), 8.6 (1H, broad s), 13.9 (1H, broad s).

Example 75-[4-(1-Hydroxyethyl)piperidine-1-carbonyl]-2H-pyrazole-3-carboxylicAcid {2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide a)1-(Pyridin-4-yl)ethanol

To a stirred solution of 4-acetylpyridine (2.50 g, 20.6 mmol) inmethanol (25 ml) sodium borohydride (1.56 g, 41.2 mmol) was added inportions. After stirring overnight at RT water was added and the mixturewas evaporated to dryness in vacuo. The product was taken into ethylacetate. The solvent was evaporated to give 2.53 g of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆): 1.32 (3H, d), 4.69-4.75 (1H, m),5.38 (1H, d), 7.34 (2H, d), 8.49 (2H, d).

b) 1-(Piperidin-4-yl)ethanol

1-(Pyridin-4-yl)ethanol (2.53 g, 20.5 mmol) was dissolved in acetic acid(20 ml) and hydrogenated in the presence of platinum(IV) oxide (0.19 g)at 1 atm at RT. The catalyst was removed by filtration through Celite®and the filtrate was concentrated in vacuo to yield crude1-(pyridin-4-yl)ethanol as an acetate salt which was triturated in ethylacetate. The water solution of the acetate salt was made basic (pH>10)with sodium hydroxide and 1-(pyridin-4-yl)ethanol as a base wasextracted into ethyl acetate. The extracts were concentrated in vacuo.¹H NMR (400 MHz, DMSO-d₆): 1.00 (3H, d), 0.94-1.11 (2H, m), 1.14-1.23(1H, m), 1.44 (1H, m), 1.66 (1H, m), 2.37 (2H, m), 2.91 (2H, m), 3.30(1H, quintet), 4.23 (1H, broad s).

c) 5-[4-(1-Hydroxyethyl)piperidine-1-carbonyl]-2H-pyrazole-3-carboxylicAcid {2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

The title compound was prepared as as in Example 1 starting from5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylicacid and 1-(piperidin-4-yl)ethanol. The crude product was purified byflash chromatography using CH₂Cl₂-MeOH as a gradient eluent(100:0-90:10). ¹H NMR (400 MHz, CDCl₃): 1.22 (3H, d), 1.30-1.41 (3H, m),1.62 (1H, m), 1.77 (1H, m), 2.00 (1H, m), about 2.78 (1H, m), 3.01 (2H,t), about 3.18 (1H, m), about 3.64 (1H, m), 3.77 (2H, q), about 4.48(1H, m), about 4.75 (1H, m), 6.20 (1H, d), 6.58 (1H, d), 7.02 (1H, s),about 7.28 (1H, broad s), 7.40 (1H, distorted d), 7.43 (1H, distorteddd), 7.75 (1H, d), 11.44 (1H, broad s).

Example 8N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-(morpholine-4-carbonyl)-1H-pyrazole-5-carboxamide

The title compound was prepared as in Example 1 starting from morpholineand5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylicacid. Crude product was purified by chromatography (CombiFlash, 1^(st)column silica, eluent: 0-10% MeOH/DCM; 2^(nd) column C-18 RP, eluent:0-100% MeCN/water) to give 505 mg (17%) of the title compound. ¹H-NMR(400 MHz; d6-DMSO): δ 2.95 (t, 1H), 3.56 (q, 1H), 3.62 (br s, 6H), 3.90(br s, 2H), 6.34 (d, 1H), 7.02 (d, 1H), 7.08 (s, 1H), 7.62 (m, 2H), 7.85(d, 1H), 8.61 (s, 1H), 13.94 (s, 1H).

Example 9N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-(4-methylpiperazine-1-carbonyl)-1H-pyrazole-5-carboxamide

The title compound was synthesized as in Example 1 starting from1-methylpiperazine and5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylicacid. Crude product was purified by chromatography (CombiFlash, silicacolumn, eluent 0-10% MeOH/DCM) and crystallized from DCM/heptane to give1.06 g (35%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 2.19(s, 3H), 2.33 (br s, 4H), 2.95 (t, 2H), 3.56 (q, 2H), 3.62 (br s, 2H),3.85 (br s, 2H), 6.34 (d, 1H), 7.02 (d, 1H), 7.07 (br s, 1H), 7.60 (dd,1H), 7.63 (d, 1H), 7.84 (d, 1H), 8.61 (s, 1H), 13.92 (s, 1H).

Example 105-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethylcarbamyl)pyrazine-2-carboxylicAcid

Pyrazine-2,5-dicarboxylic acid (0.58 g; 3.42 mmol), anhydrous HOBt (0.69g; 5.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.98 g: 5.13 mmol) were added to 5 ml of DCM.2-(5-(3,4-dichlorophenyl)furan-2-yl)-ethanamine hydrochloride (1.0 g;3.42 mmol) and DIPEA (0.89 ml; 5.13 mmol) were dissolved in 5 ml of DCMand added dropwise to the previous mixture. The reaction mixture wasstirred overnight after which pyrazine-2,5-dicarboxylic acid (0.58 g;1.59 mmol) and DIPEA (0.60 ml; 3.42 mmol) were added and the mixture wasagain stirred for 5 h. Anhydrous HOBt (0.69 g; 5.13 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.98 g:5.13 mmol) and DIPEA (0.89 ml; 5.13 mmol) were again added to drive thereaction to completion. After overnight stirring the mixture was dilutedwith 20 ml of DCM and washed with 3×10 ml water. The organic phase wasdried over Na₂SO₄, filtered and used as such without furtherpurification.

Example 11N-2-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-N-5-(2-hydroxyethyl)pyrazine-2,5-dicarboxamide

5-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethylcarbamoyl)pyrazine-2-carboxylicacid (0.12 g; 0.30 mmol), anhydrous HOBt (0.15 g; 1.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.085 g:0.44 mmol) and DIPEA (0.077 ml; 0.44 mmol) were dissolved in 2.5 ml ofDCM. To this a solution of 2-aminoethanol (0.018 ml; 0.3 ml) in 2.5 mlof DCM was added and the mixture was stirred overnight. The mixture wasdiluted with 10 ml of DCM and washed with 3×5 ml water. The water phaseswere then extracted with EtOAc, the organic phase dried over Na₂SO₄,filtered and evaporated to dryness. The product was purified with flashchromatography. The combined fractions gave 6 mg of the product. ¹H-NMR(400 MHz; d6-DMSO): δ 3.01 (t, 2H), 3.38-3.43 (m, 2H), 3.52-3.57 (m,2H), 3.64-3.69 (m, 2H), 4.81 (t, 1H), 6.36 (d, 1H), 7.02 (d, 1H),7.58-7.64 (m, 2H), 7.80 (d, 1H), 8.91-8.94 (t, 1H), 9.19 (d, 1H), 9.21(d, 1H), 9.26-9.29 (t, 1H).

Example 12 1,5-Dimethyl-1H-pyrazole-3-carboxylic Acid{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (100 mg, 0.71 mmol) wasdissolved in dry DMF (2 ml). EDCI (205 mg, 1.1 mmol), HOBt (145 mg, 1.1mmol) and DIPEA (0.19 ml, 141 mg, 1.1 mmol) were added at RT. Thesolution was stirred for 30 min. Then,2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride (313 mg,1.1 mmol) dissolved in the mixture of dry DMF (4 ml) and DIPEA (0.19 ml,141 mg, 1.1 mmol) was added to the solution at RT. After stirringovernight water was added. The product was extracted into ethyl acetate.The organic phase was washed with water, dried and evaporated. The crudeproduct was purified by flash chromatography using CH₂Cl₂-MeOH as agradient eluent (100:0-95:5). Another purification was done also byflash chromatography using CH₂Cl₂-MeOH as a gradient eluent(100:0-99.7:0.3). The product was triturated in heptane-CH₂Cl₂ at RT. ¹HNMR (400 MHz, DMSO-d₆): 2.26 (3H, s), 2.92 (2H, t), 3.52 (2H, m), 3.76(3H, s), 6.31 (1H, d), 6.38 (1H, s), 7.01 (1H, d), 7.60 (1H, distorteddd), 7.64 (1H, distorted d), 7.83 (1H, d), 8.09 (1H, t).

Example 13 5-Furan-2-yl-1-phenyl-1H-pyrazole-3-carboxylic Acid{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

The title compound was prepared as in Example 12 starting from5-(2-furyl)-1-phenyl-1H-pyrazole-3-carboxylic acid and2-[5-(3,4-dichlorophenyl)furan-2-yl]-ethylamine hydrochloride. The crudeproduct was purified twice by flash chromatography using firstCH₂Cl₂-MeOH as a gradient eluent (100:0-99:1). Then another purificationby flash chromatography was done by using heptane/EtOAc (8:2) as aneluent. ¹H NMR (400 MHz, DMSO-d₆): 2.96 (2H, t), 3.58 (2H, m), 6.16 (1H,d), 6.34 (1H, d), 6.51 (1H, dd), 7.01 (1H, d), 7.07 (1H, s), 7.45-7.48(2H, m), 7.54-7.56 (4H, m), 7.61 (1H, distorted dd), 7.73 (1H, d), 7.84(1H, d), 8.49 (1H, t, ³J=5.9 Hz).

Example 14 1-Methyl-1H-indazole-3-carboxylic Acid{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

The title compound was prepared as in Example 12 starting fromN-methyl-indazole-3-carboxylic acid and2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride. The crudeproduct was purified by flash chromatography using heptane/EtOAc as agradient eluent (9:1-8:2). ¹H NMR (400 MHz, DMSO-d₆): 3.00 (2H, t), 3.64(2H, m), 4.12 (3H, s), 6.36 (1H, d), 7.01 (1H, d), 7.26 (1H, m), 7.46(1H, m), 7.600 (1H, s), 7.602 (1H, s), 7.72 (1H, d), 7.83 (1H, s), 8.16(1H, d), 8.48 (1H, t).

Example 15 1H-Imidazole-4-carboxylic Acid{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

The title compound was prepared as in Example 12 starting from4-imidazolecarboxylic acid and2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride. The crudeproduct was purified by flash chromatography using CH₂Cl₂/MeOH as agradient eluent (100:0-99.6:0.4). The product was triturated in ethylacetate. ¹H NMR (400 MHz, DMSO-d₆): 2.93 (2H, t), 3.55 (2H, m), 6.33(1H, d), 7.01 (1H, d), 7.59 (1H, s), 7.63 (2H, s), 7.71 (1H, s), 7.87(1H, s), 8.05 (1H, broad s), 12.43 (1H, broad s).

Example 16 2-Methyl-1H-imidazole-4-carboxylic Acid{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide Hydrochloride

The title compound was prepared as in Example 12 starting from2-methyl-1H-imidazole-4-carboxylic acid and2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride. The crudeproduct was purified by flash chromatography using CH₂Cl₂/MeOH as agradient eluent (100:0-97:3). The product was dissolved in DCM, ethylacetate saturated with hydrogen chloride was added and the precipitatedproduct as a hydrogen chloride salt was filtered. Recrystallization fromMeOH/EtOAc. The HCl salt: ¹H NMR (400 MHz, MeOH-d₄): 2.62 (3H, s), 3.02(1H, t), 3.69 (1H, t), 6.26 (1H, d), 6.76 (1H, d), 7.49 (1H, distortedd), 6.53 (1H, distorted dd), 7.71 (1H, d), 7.82 (1H, s).

Example 17 1H-Indazole-3-carboxylic Acid{2-[5-(3,4-dichlorophenyl)-furan-2-yl]-ethyl}-amide a)(E)-2-(5-(3,4-dichlorophenyl)furan-2-yl)ethenamine

To a stirred solution of 5-(3,4-dichlorophenyl)furfural (1.18 g, 4.89mmol) in acetic acid (30 ml) was added nitromethane (0.535 ml, 9.78mmol) and ammonium acetate (1.13 g, 14.7 mmol). The reaction mixture washeated at 80° C. for 4.5 h. Cooled reaction mixture was poured onto icewater (30 ml) and thus formed precipitate was filtered, washed withwater and dried under vacuum to give 1.15 g (83%) of the title compound.¹H-NMR (400 MHz; d6-DMSO): δ 7.37 (d, 1H), 7.43 (d, 1H), 7.76 (d, 1H),7.95 (dd, 1H), 8.03 (d, 1H), 8.19 (d, 1H), 8.31 (d, 1H).

b) 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine

To a suspension of lithium aluminium hydride (0.939 g, 24.8 mmol) in THF(20 ml) under nitrogen atmosphere at 0° C. was added slowly a solutionof (E)-2-(5-(3,4-dichlorophenyl)furan-2-yl)ethenamine in THF (20 ml).Reaction mixture was stirred at RT for 1 h. Some methanol was addedslowly to the mixture followed by addition of water. The mixture wasevaporated, and the solid residue was extracted with EtOAc (3×).Combined EtOAc fractions were washed with 2M NaOH and brine. Organicphase was dried over Na₂SO₄, evaporated and purified by chromatography(CombiFlash, silica column, eluent: 10-20% MeOH/DCM) to give 227 mg(11%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 2.74 (t, 2H),2.85 (t, 2H), 6.29 (d, 1H), 7.03 (d, 1H), 7.62 (dd, 1H), 7.63 (d, 1H),7.88 (d, 1H).

c) 1H-Indazole-3-carboxylic Acid{2-[5-(3,4-dichlorophenyl)-furan-2-yl]-ethyl}-amide

Indazole-3-carboxylic acid (30 mg; 0.182 mmol), DCC (56 mg, 0.273 mmol)and DMAP (2 mg) were dissolved in DCM:DMF (1:1, 4 ml).2-(5-(3,4-dichloro-phenyl)furan-2-yl)ethanamine (46 mg, 0.182 mmol) wasadded and the reaction mixture was stirred for overnight at RT. DCM (30ml) was added and organic layer washed with water (3×15 ml). Combinedorganic phases were dried over Na₂SO₄, evaporated and purified bychromatography (silica column, eluent: 1% MeOH/DCM) to give 25 mg (34%)of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 3.00 (t, 2H), 3.63(q, 2H), 6.37 (d, 1H), 7.02 (d, 1H), 7.23 (t, 1H), 7.41 (t, 1H), 7.60(d, 1H), 7.61 (d, 2H), 7.85 (d, 1H), 8.16 (d, 1H), 8.54 (d, 1H), 13.56(s, 1H).

Example 18 5-Tert-Butyl-2H-pyrazole-3-carboxylic Acid{2-[5-(3,4-dichlorophenyl)-furan-2-yl]-ethyl}-amide

The title compound was synthesized as in Example 17 starting from5-tert-butyl-2H-pyrazole-3-carboxylic acid and2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine. Crude product waspurified by chromatography (silica column, eluent: 3% MeOH/DCM) to give53 mg (33%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.27 (s,9H), 2.97 (t, 2H), 3.54 (q, 2H), 6.33 (m, 1H), 6.39 (br s, 1H), 7.02 (d,1H), 7.62 (m, 2H), 7.86 (d, 1H), 8.20 (s, 1H), 12.88 (s, 1H).

Example 193-Tert-butyl-N-(1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-yl)-1H-pyrazole-5-carboxamidea) (E)-1-(5-(3,4-dichlorophenyl)furan-2-yl)prop-1-en-2-amine

To a stirred solution of 5-(3,4-dichlorophenyl)furfural (1.21 g, 5.0mmol) in acetic acid (15 ml) was added nitroatehane (0.720 ml, 10.0mmol) and ammonium acetate (1.16 g, 15.0 mmol). The mixture was stirredat 80° C. overnight. The reaction mixture was poured to ice water. Theresulting precipitate was filtered, washed with water and dried undervacuum to obtain 1.38 g (93%) of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 2.62 (s, 3H), 7.37 (d, 1H), 7.46 (d, 1H), 7.79 (m, 2H), 7.98(s, 1H), 8.09 (d, 1H).

b) 1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-amine Hydrochloride

To a solution of(E)-1-(5-(3,4-dichlorophenyl)furan-2-yl)prop-1-en-2-amine (2.72 g, 9.12mmol) in MeOH (135 ml), EtOAc (100 ml) and 6.5% HCl (g) in MeOH (32 ml)was added 10% Pd/C (1.09 g). The mixture was hydrogenated under pressure(3.3 bar, Parr hydrogenating apparatus) for 7 h. The reaction mixturewas filtered through Celite, evaporated and purified by chromatography(CombiFlash, silica column, eluent: 5-20% MeOH/DCM) to yield 0.811 g(29%) of the title compound as an HCl salt. ¹H-NMR (400 MHz; d6-DMSO): δ1.21 (d, 3H), 2.90 (dd, 1H), 3.04 (dd, 1H), 3.55 (q, 1H), 6.44 (d, 1H),7.09 (d, 1H), 7.68 (m, 2H), 7.93 (m, 1H).

c)3-Tert-butyl-N-(1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

5-Tert-butyl-2H-pyrazole-3-carboxylic acid (94 mg; 0.55 mmol) wasdissolved in DCM:DMF (4:1, 5 ml). DCC (172 mg; 0.83 mmol) was added.1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-amine (149 mg; 0.55 mmol)was dissolved in 2 ml of DCM and TEA (77 μl, 0.55 mmol) and theresulting solution was added to the reaction mixture. The reactionmixture was stirred overnight at RT. Then DCM (50 ml) was added andorganic phase was washed with water (2×30 ml). The organic phase wasdried over Na₂SO₄, evaporated and purified by chromatography(CombiFlash, 1^(st) column silica, eluent: 7.5-100% EtOAc/heptane;2^(nd) column silica, eluent: 0-5% MeOH/DCM) to give 35 mg (15%) of thetitle compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 1.27 (s, 9H),2.88 (dd, 1H), 2.98 (dd, 1H), 4.33 (quintet, 1H), 6.29 (d, 1H), 6.33 (s,1H), 7.00 (d, 1H), 7.60 (m, 2H), 7.83 (d, 1H), 7.89 (d, 1H), 12.84 (s,1H).

Example 20N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide

To a stirred solution of 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid(1.78 g, 9.42 mmol) in DCM (10 ml) was added DIPEA (2.46 ml, 14.1 mmol),EDCI (2.71 g, 9.42 mmol) and HOBt (1.91, 14.1 mmol).2-(5-(3,4-dichlorophenyl)furan-2-yl)-ethanamine hydrochloride (2.75 g,9.42 mmol) was dissolved in DCM (15 ml) and DIPEA (1.64 ml, 9.42 mmol).The resulting solution was added to the reaction mixture, which wasstirred at RT overnight. The reaction mixture was diluted with DCM andwashed with saturated aqueous NaHCO₃ solution and water. The organicphase was dried over Na₂SO₄, evaporated and purified by chromatography(CombiFlash, silica column, eluent 0-15% MeOH/DCM). Product containingfractions were collected, evaporated and crystallized from DCM andre-crystallized from 2% MeOH/DCM and heptane. Thus, 1.18 g (29%) of thetitle compound was obtained. ¹H-NMR (400 MHz; d6-DMSO): δ 2.97 (t, 2H),3.59 (q, 2H), 6.35 (d, 1H), 7.03 (d, 1H), 7.33 (s, 1H), 7.62 (d, 2H),7.75 (m, 2H), 7.84 (t, 1H), 8.57 (br s, 1H), 8.63 (m, 2H), 13.95 (s,1H).

Example 213-tert-Butyl-N-(2-(5-(3,4-dicyanophenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide

To a stirred solution of 5-tert-Butyl-2H-pyrazole-3-carboxylic acid{2-[5-(3,4-dichloro-phenyl)-furan-2-yl]-ethyl}-amide of Example 18 (128mg, 0.315 mmol) in DMF/water (99:1, 1 ml) was added zinc cyanide (81 mg,0.693 mmol), S-Phos (26 mg, 0.063 mmol) and Pd₂(dba)₃ (23 mg, 0.025mmol). The reaction mixture was heated by a microwave reactor at 150° C.for 40 min. 1.0 M NaOH (20 ml) was added and the mixture was extractedwith EtOAc (3×20 ml). Combined organic phases were dried over Na₂SO₄,evaporated and purified by chromatography (CombiFlash, 1^(st) columnsilica: eluent 0-100% EtOAc/heptane; 2^(nd) column C-18 RP: eluent0-100% MeCN/water) to give 25 mg (20%) of the title compound. ¹H-NMR(400 MHz; d6-DMSO): δ 1.27 (s, 9H), 2.96 (t, 2H), 3.57 (q, 2H), 6.35 (brs, 1H), 6.44 (d, 1H), 7.31 (d, 1H), 8.07 (dd, 1H), 8.11 (d, 1H), 8.19(br s, 1H), 8.38 (d, 1H), 12.87 (br s, 1H).

Example 22N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-methyl-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 20 startingfrom 3-methyl-1H-pyrazole-5-carboxylic acid and2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine hydrochloride. Crudeproduct was purified by chromatography (CombiFlash, silica column,eluent: 0-100% EtOAc/heptane) to obtain 301 mg (28%) of the titlecompound. ¹H-NMR (400 MHz; d6-DMSO): δ 2.25 (s, 3H), 2.92 (t, 2H), 3.53(q, 2H), 6.32 (d, 1H), 6.34 (s, 1H), 7.01 (d, 1H), 7.63 (m, 2H), 7.85(s, 1H), 8.16 (t, 1H), 13.86 (s, 1H).

Example 23N-(2-(5-(3,4-dicyanophenyl)furan-2-yl)ethyl)-3-methyl-1H-pyrazole-5-carboxamide

The title compound was prepared as in Example 21, but starting fromN-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-methyl-1H-pyrazole-5-carboxamide.Crude product was purified by chromatography (CombiFlash, 1^(st) columnsilica, eluent: 0-10% MeOH/DCM; 2^(nd) column C-18 RP, eluent: 0-100%MeCN/water) to obtain 45 mg (16%) of the title compound. ¹H-NMR (400MHz; d6-DMSO): δ 2.24 (s, 3H), 2.96 (t, 2H), 3.55 (q, 2H), 6.35 (s, 1H),6.43 (d, 1H), 7.31 (d, 1H), 8.07 (dd, 1H), 8.12 (d, 1H), 8.20 (br s,1H), 8.34 (d, 1H), 12.87 (s, 1H).

Example 24(S/R)—N-(1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-yl)-3-methyl-1H-pyrazole-5-carboxamide

The title compound was prepared as a racemate using the method ofExample 19, but starting from 3-methyl-1H-pyrazole-5-carboxylic acid and1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-amine hydrochloride. Thus,79 mg (32%) of the title compound was obtained. The enantiomers wereseparated by chromatography (SFC Minigram, Mettler Toledo) to obtain 16mg of the other (optical purity 98.8%) (=Compound 24A) and 16 mg of theother (optical purity 98.3%) (=Compound 24B) enantiomer. The absoluteconfiguration of the separated enantiomers was not analysed.

Compound 24A: ¹H-NMR (400 MHz; CDCl₃): δ 1.26 (d, 3H), 2.34 (s, 3H),2.91 (dd, 1H), 3.01 (dd, 1H), 4.52 (m, 1H), 6.20 (d, 1H), 6.56 (s, 1H),6.57 (d, 1H), 7.12 (d, 1H), 7.38 (d, 1H), 7.41. (dd, 1H), 7.78 (d, 1H),10.26 (s, 1H).

Compound 24B: ¹H-NMR (400 MHz; CDCl₃): δ 1.26 (d, 3H), 2.34 (s, 3H),2.91 (dd, 1H), 3.01 (dd, 1H), 4.52 (m, 1H), 6.20 (d, 1H), 6.56 (s, 1H),6.57 (d, 1H), 7.12 (d, 1H), 7.38 (d, 1H), 7.41. (dd, 1H), 7.78 (d, 1H),10.31 (s, 1H).

Example 25(S/R)—N-(1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-yl)-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared as a racemate using the method ofExample 19, but starting from 5-pyridin-4-yl-4H-pyrazole-3-carboxylicacid and 1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-aminehydrochloride. Thus, 90 mg (31%) of the title compound was obtained. Theenantiomers were separated by chromatography (SFC Minigram, MettlerToledo) to obtain 16 mg of the other (optical purity 100%) (=Compound25A) and 11 mg of the other (optical purity 100%) (=Compound 25B)enantiomer. The absolute configuration of the separated enantiomers wasnot analysed.

Compound 25A: ¹H-NMR (400 MHz; d6-DMSO): δ 1.24 (d, 3H), 2.95 (m, 2H),4.35 (m, 1H), 6.31 (d, 1H), 7.00 (d, 1H), 7.35 (s, 1H), 7.58 (s, 2H),7.73 (m, 2H), 7.93 (s, 1H), 8.33 (br s, 1H), 8.63 (d, 2H), 13.88 (s,1H).

Compound 25B: ¹H-NMR (400 MHz; d6-DMSO): δ 1.24 (d, 3H), 2.95 (m, 2H),4.35 (m, 1H), 6.31 (d, 1H), 7.00 (d, 1H), 7.35 (s, 1H), 7.58 (s, 2H),7.73 (m, 2H), 7.79 (s, 1H), 8.33 (br s, 1H), 8.63 (d, 2H), 13.88 (s,1H).

Example 26 1-(Pyridin-2-yl)-1H-imidazole-4-carboxylic Acid{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide

The title compound was synthesized from 1H-Imidazole-4-carboxylic acid{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide of Example 15 and2-bromopyridine by the method described by A. K. Verma et al.Tetrahedron Lett. 48 (2007) 4207. Purification by flash chromatographyusing CH₂Cl₂/MeOH as a gradient eluent (100:0-99.9:0.1) gave a productwhich was triturated in EtOAc at RT to afford the desired product. ¹HNMR (400 MHz, DMSO-d₆): 2.96 (2H, t), 3.59 (2H, m), 6.35 (1H, d), 7.03(1H, d), 7.44 (1H, m), 7.63 (2H, s), 7.84 (1H, s), 7.95 (1H, distortedd), 8.05 (1H, m), 8.33 (1H, t), 8.43 (1H, d), 8.54 (1H, m), 8.64 (1H, d,⁴J=1.1 Hz).

Example 27N-(2-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)ethyl)-3-methyl-1H-pyrazole-5-carboxamidea)2-(2-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)ethyl)isoindoline-1,3-dione

To a cooled (0° C.) suspension of sodium hydride (96 mg, 2.4 mmol) inDMF (1.0 ml) was added 3-(3,4-dichlorophenyl)-1H-pyrazole (0.426 g, 2.0mmol) as a solution in DMF (2.0 ml). The reaction mixture was stirred atRT for 45 min. To cooled (0° C.) reaction mixture was addedN-(2-bromoethyl)phthalimide (0.610 g, 2.4 mmol) as a solution in DMF(1.0 ml). The reaction mixture was stirred at RT overnight. Water (100ml) was added, and the mixture was extracted with DCM (3×50 ml).Combined organic phases were dried over Na₂SO₄ and purified bychromatography (CombiFlash, C-18 RP column, eluent: 0-100% MeCN/water)to obtain 0.155 g (20%) of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 3.98 (t, 2H), 4.26 (t, 2H), 6.74 (d, 1H), 7.45 (dd, 1H),7.50 (d, 1H), 7.55 (d, 1H), 7.82 (m, 5H).

b) 2-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)ethanamine

To a stirred solution of2-(2-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)ethyl)-isoindoline-1,3-dione(155 mg, 0.40 mmol) in EtOH (4.0 ml) was added hydrazine hydrate (0.194ml, 4.0 mmol). The reaction mixture was refluxed for 1 h and left tocool down to RT. Water (20 ml) was added and the mixture was extractedwith DCM (3×20 ml). Combined organic phases were dried over Na₂SO₄ andevaporated to yield quantitative amount of the title compound (102 mg,100%). Product was used in the next step without analysis.

c)N-(2-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)ethyl)-3-methyl-1H-pyrazole-5-carboxamide

To a stirred solution of 3-methyl-1H-pyrazole-5-carboxylic acid (104 mg,0.83 mmol) in DCM (2.0 ml) was added DIPEA (0.144 ml, 0.83 mmol), EDCI(159 mg, 0.83 mmol) and HOBt (112 mg, 0.83 mmol). After 10 min2-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)ethanamine (102 mg, 0.40 mmol)was added to the reaction mixture as a solution in DCM (2.0 ml). Thereaction mixture was stirred at RT overnight. The reaction mixture wasdiluted with DCM and washed with saturated aqueous NaHCO₃ solution andwater. The organic phase was dried over Na₂SO₄, evaporated and purifiedby chromatography (CombiFlash, 1^(st) column silica, eluent: 0-10%MeOH/DCM; 2^(nd) column C-18 RP, eluent: 0-100% MeCN/water) to obtain 65mg (45%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.24 (s,3H), 3.64 (q, 2H), 4.31 (t, 2H), 6.36 (s, 1H), 6.81 (d, 1H), 7.65 (d,1H), 7.77 (d, 1H), 7.80 (dd, 1H), 8.00 (d, 1H), 8.23 (s, 1H), 12.88 (s,1H).

Example 28N-(2-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamidea) 2-methyl-4-(1H-pyrazol-3-yl)benzonitrile

The title compound was synthesized using the method of Example 34(b),but starting from 4-bromo-2-methylbenzonitrile and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.1H-NMR (400 MHz; CDCl₃): δ 2.60 (s, 3H), 6.69 (d, 1H), 7.64 (m, 2H),7.70 (d, 1H), 7.78 (s, 1H), 10.47 (br s, 1H).

b)4-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile

2-Methyl-4-(1H-pyrazol-3-yl)benzonitrile (0.949 g, 5.2 mmol) was reactedwith N-(2-bromoethyl)phthalimide (1.58 g, 6.2 mmol) using the method ofExample 27(a). Crude product was purified by chromatography (CombiFlash,silica column, eluent: 0-100% EtOAc/heptane) to yield 0.590 g (32%) ofthe title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.36 (s, 3H), 3.99 (t,2H), 4.44 (t, 2H), 6.76 (d, 1H), 7.44 (s, 1H), 7.46 (m, 1H), 7.62 (d,1H), 7.83 (m, 5H).

c) 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile

4-(1-(2-(1,3-Dioxoisoindolin-2-yl)ethyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile(0.590 g, 1.66 mmol) was treated with hydrazine hydrate using the methodof Example 27(b). Thus, 362 mg (96%) of the title compound was obtained.1H-NMR (400 MHz; d6-DMSO): δ 2.52 (s, 3H), 2.95 (t, 2H), 4.13 (t, 2H),6.84 (d, 1H), 7.77 (m, 2H), 7.82 (d, 1H), 7.89 (m, 1H).

d)N-(2-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (303 mg, 1.60 mmol) and4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (362 mg, 1.60mmol) using the method of Example 34(d). Crude product was purified bychromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) toobtain 44 mg (6%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ2.49 (s, 3H), 3.71 (q, 2H), 4.37 (t, 2H), 6.84 (d, 1H), 7.31 (s, 1H),7.74 (m, 2H), 7.70 (s, 1H), 7.79 (dd, 1H), 7.83 (d, 1H), 7.88 (s, 1H),8.55 (br s, 1H), 8.63 (m, 2H), 13.99 (s, 1H).

Example 29(S)—N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamidea)(S)-4-(1-(2-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile

2-Methyl-4-(1H-pyrazol-3-yl)benzonitrile (2.35 g, 12.2 mmol) was reactedwith (S)-2-(1-bromopropan-2-yl)isoindoline-1,3-dione (3.61 g, 13.5 mmol)using the method of Example 27(a). Crude product was purified bychromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane)to yield 1.15 g (25%) of the title compound. 1H-NMR (400 MHz; CDCl₃): δ1.59 (d, 3H), 2.47 (s, 3H), 4.41 (m, 1H), 4.83 (m, 2H), 6.46 (d, 1H),7.39 (m, 2H), 7.47 (m, 2H), 7.69 (m, 2H), 7.78 (m, 2H).

b) (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile

(S)-4-(1-(2-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile(481 mg, 1.3 mmol) was treated with hydrazine hydrate using the methodof Example 27(b). Crude product was purified by chromatography(CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 59 mg(19%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 0.96 (d, 3H),2.52 (s, 3H), 3.23 (m, 1H), 4.00 (m, 2H), 6.85 (d, 1H), 7.77 (m, 2H),7.81 (d, 1H), 7.89 (m, 1H).

c)(S)—N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (47 mg, 0.25 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (59 mg,0.25 mmol) using the method of Example 34(d). Crude product was purifiedby chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) toobtain 41 mg (40%) of the title compound. 1H-NMR (400 MHz; MeOD): δ 1.24(d, 3H), 2.52 (s, 3H), 4.32 (m, 2H), 4.53 (m, 1H), 6.59 (d, 1H), 7.15(m, 1H), 7.36 (s, 2H), 7.53 (d, 1H), 7.58 (m, 2H), 7.70 (m, 2H), 8.53(br s, 1H), 8.56 (d, 1H).

Example 30(R)—N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamidea) (R)-2-(1-hydroxypropan-2-yl)isoindoline-1,3-dione

D-Alaninol (3.90 ml, 50 mmol) and phthalic anhydride (7.41 g, 50 mmol)were heated at 160° C. for 30 min. To cooled reaction mixture was addedice water and DCM. Organic phase was collected and the water phase wasextracted with DCM. Combined organic phases were dried over Na₂SO₄ andevaporated to obtain 8.75 g (85%) of the title compound. 1H-NMR (400MHz; d6-DMSO): δ 1.32 (d, 3H), 3.54 (m, 1H), 3.84 (m, 1H), 4.26 (m, 1H),4.91 (m, 1H), 7.84 (m, 4H).

b) (R)-2-(1-bromopropan-2-yl)isoindoline-1,3-dione

(R)-2-(1-hydroxypropan-2-yl)isoindoline-1,3-dione (8.75 g, 43 mmol) andphosphorus tribromide (2.73 ml, 29 mmol) were heated at 175° C. for 50min. To cooled reaction mixture was added ice (50 ml). Thus formedprecipitate was filtered, washed with water and dried under vacuum toobtain 11.1 g (97%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ1.50 (d, 3H), 3.85 (m, 1H), 4.01 (m, 1H), 4.49 (m, 1H), 7.88 (m, 4H).

c)(R)-4-(1-(2-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile

2-Methyl-4-(1H-pyrazol-3-yl)benzonitrile (2.23 g, 12.2 mmol) was reactedwith (R)-2-(1-bromopropan-2-yl)isoindoline-1,3-dione (3.92 g, 14.6 mmol)using the method of Example 27(a). Crude product was purified bychromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane)to yield 0.753 g (17%) of the title compound. Product was used in thenext step without analysis.

d) (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile

(R)-4-(1-(2-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile(753 mg, 2.0 mmol) was treated with hydrazine hydrate using the methodof Example 27(b). Crude product was purified by chromatography(CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 82 mg(17%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 0.96 (d, 3H),2.52 (s, 3H), 3.22 (m, 1H), 3.99 (m, 2H), 6.84 (d, 1H), 7.77 (m, 2H),7.81 (d, 1H), 7.89 (m, 1H).

e)(R)—N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (13 mg, 0.069 mmol) and(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (17 mg,0.071 mmol) using the method of Example 34(d). Crude product waspurified by chromatography (CombiFlash, silica column, eluent: 0-20%MeOH/DCM) to obtain 19 mg (67%) of the title compound. 1H-NMR (400 MHz;d6-DMSO): δ 1.17 (d, 3H), 2.48 (s, 3H), 4.31 (m, 2H), 4.47 (m, 1H), 6.82(d, 1H), 7.31 (s, 1H), 7.75 (m, 4H), 7.81 (d, 1H), 7.85 (s, 1H), 8.40(d, 1H), 8.63 (m, 2H), 13.92 (br s, 1H).

Example 31N-(2-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)ethyl)-3-methyl-1H-pyrazole-5-carboxamide

The title compound was synthesized as using the method of Example 28(d)starting from 3-methyl-1H-pyrazole-5-carboxylic acid. Crude product waspurified by chromatography (CombiFlash, 1^(st) column silica, eluent:0-15% MeOH/DCM; 2^(nd) column C-18 RP, eluent: 0-100% MeCN/water) toobtain 39 mg (42%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ2.24 (s, 3H), 2.52 (s, 3H), 3.65 (q, 2H), 4.33 (t, 2H), 6.36 (s, 1H),6.83 (d, 1H), 7.79 (m, 3H), 7.88 (s, 1H), 8.24 (br s, 1H), 12.85 (br s,1H).

Example 32(S)—N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was synthesized using the method of Example 29, butreplacing 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid with5-(2-furyl)-4H-pyrazole-3-carboxylic acid. Crude product was purified bychromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane)to obtain 39 mg (75%) of the title compound. 1H-NMR (400 MHz; d6-DMSO):δ 1.14 (d, 3H), 2.49 (s, 3H), 4.30 (m, 2H), 4.45 (m, 1H), 6.61 (m, 1H),6.80 (s, 1H), 6.82 (d, 1H), 6.91 (s, 1H), 7.76 (m, 3H), 7.80 (d, 1H),7.85 (s, 1H), 8.36 (d, 1H), 13.69 (s, 1H).

Example 33(R)—N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(morpholine-4-carbonyl)-1H-pyrazole-5-carboxamide

The title compound was synthesized using the method of Example 30, butreplacing 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid with3,5-pyrazoledicarboxylic acid. Thus obtained(R)-5-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-pyrazole-3-carboxylicacid was coupled with morpholine according to synthesis of5-(piperazine-1-carbonyl)-2H-pyrazole-3-carboxylic acid{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide, Example 1, butreplacing piperazine with morpholine. Crude product was purified bychromatography (CombiFlash, 1^(st) column silica, eluent: 0-10%MeOH/DCM; 2^(nd) column C-18 RP, eluent: 0-100% MeCN/water) to obtain 24mg (45%) of the title compound. 1H-NMR (400 MHz; CDCl₃): δ 1.25 (d, 3H),2.60 (s, 3H), 3.79 (m, 8H), 4.29 (dd, 1H), 4.42 (dd, 1H), 4.60 (m, 1H),6.61 (d, 1H), 7.02 (s, 1H), 7.47 (d, 1H), 7.63 (m, 2H), 7.72 (d, 1H),7.79 (s, 1H), 11.09 (s, 1H).

Example 34(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamidea) 2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile

1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(6.5 g; 23.28 mmol) and 4-bromo-2-chlorobenzonitrile (4 g; 18.48 mmol)were dissolved in THF (65 ml). To this mixturebis(triphenylphosphine)palladium(II) chloride (0.65 g; 0.92 mmol),sodium carbonate (4.7 g; 44.3 mmol) and 18 ml of water were added andthe reaction mixture was stirred at 35° C. for 2.5 h. The solvents weredistilled to almost dryness and water (48 ml) was added. After 30 min ofstirring the precipitated product was filtered and 32 ml of ethanol wasadded to the precipitation. The suspension was stirred for 15 min at RTand 30 min at −10° C. before filtering to give 3.7 g of the product.¹H-NMR (400 MHz; d6-DMSO): δ 1.63-1.54 (m, 3H), 1.84-1.80 (m, 1H),1.97-1.94 (m, 1H), 2.39-2.35 (m, 1H), 3.63-3.57 (m, 1H), 3.99 (m, 1H),5.32-5.27 (m, 1H), 6.72 (d, 1H), 7.65 (d, 1H), 7.72 (m, 1H), 7.92 (d,1H), 8.14 (d, 1H).

b) 2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile

2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile(3.67 g; 12.75 mmol) was added to 8 ml of ethanol under nitrogenatmosphere. 15.5 ml of ˜10% HCl (g) in EtOH was slowly added and thetemperature was raised to 30° C. where the mixture was stirred for 1 h.The temperature was then lowered to −10° C. and the mixture was againstirred for 30 min after which the product was precipitated as its HClsalt and was filtered and washed twice with 2 ml of ethanol. The productwas dried in vacuo at +40° C. Yield 2.8 g.2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride (2.8 g; 11.47mmol) was added to a mixture of 8 ml of water and 14 ml of MeOH undernitrogen atmosphere. To this 50% sodium hydroxide (1.5 ml; 28.7 mmol)was added keeping the temperature under 25° C. during the addition. Themixture was stirred for 2 h, the precipitate filtered and washed twicewith 3 ml of lukewarm water. The product was dried in vacuo at +40° C.Yield 1.97 g. ¹H-NMR (400 MHz; d6-DMSO): δ 6.99 (t, 1H), 7.89 (m, 1H),7.99 (d, 2H), 8.15 (s, 1H), 13.27 (s, 1H).

c) (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (4.00 g; 19.64 mmol),(S)-tert-butyl-1-hydroxypropan-2-yl carbamate (3.79 g; 21.61 mmol) andtriphenylphosphine were dissolved in dry THF under nitrogen atmosphereand stirred. Diisopropylazo-dicarboxylate (7.74 ml; 39.3 mmol) was addeddropwise and the reaction flask was cooled by ice bath. The reaction wasstirred at RT overnight (18 h) and evaporated to dryness. For Bocdeprotection 200 ml of 10% HCl/EtOH solution was added to theevaporation residue, stirred for 20 h at RT and evaporated to dryness.100 ml of water was added to the evaporation residue and washed with3×120 ml of DCM to remove reactant residues. pH of water phase wasadjusted to ˜12 by addition of 2 M NaOH, washed with 3×80 ml of DCM andorganic phase dried over Na₂SO₄. Organic phase was filtered andevaporated to give 2.605 g of the title compound.

d)(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

3-Acetyl-1H-pyrazole-5-carboxylic acid (0.59 g; 3.84 mmol) and DIPEA(1.0 ml; 5.75 mmol) were dissolved in 4 ml of dry DCM. Anhydrous HOBt(0.78 g; 5.75 mmol) and EDCI (1.10 g; 5.75 mmol) were added at RT.(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.00 g;3.84 mmol) was dissolved in 4 ml of DCM and the reaction was stirred forovernight at RT. 40 ml of DCM was added and organic layer washed with3×15 ml of water. Combined water phases were washed with 2×20 ml of DCM.Both organic phases were dried over Na₂SO₄, filtered and evaporated todryness. Both crude product fractions were combined and purified byCombiFlash (2% MeOH in DCM). Product fractions were combined andevaporated to give 497 mg of product. ¹H-NMR (400 MHz; d6-DMSO): δ 1.16(d, 3H, J=6.7 Hz), 2.49 (s, 3H), 4.31 (m, 2H), 4.46 (sept, 1H, J=6.7Hz), 6.93 (d, 1H, J=2.4 Hz), 7.31 (s, 1H), 7.81 (d, 1H, J=2.4 Hz), 7.92(d, 1H, J=7.9 Hz), 7.97 (d, 1H, J=8.1 Hz), 8.03 (d, 1H, J=1.3 Hz), 8.48(d, 1H, J=8.5 Hz), 14.16 (s, 1H).

Example 35N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-5-(morpholine-4-carbonyl)pyrazine-2-carboxamidea) 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

The title compound was prepared using the method of Example 34(c)starting from 2.3 g of 2-chloro-4-(1H-pyrazol-5-yl)benzonitrilehydrochloride, 1.7 ml dipea and 1.7 g tert-butyl 2-hydroxyethylcarbamateyielding 2.08 g of the product. ¹H-NMR (400 MHz; d₆-DMSO): δ 1.56 (s,2H), 2.97 (t, 2H), 4.13-4.17 (t, 2H), 6.97 (s, 1H), 7.87 (d, 1H),7.93-8.02 (m, 2H), 8.10 (d, 1H).

b)5-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethylcarbamoyl)pyrazine-2-carboxylicAcid

Pyrazine-2,5-dicarboxylic acid (0.53 g; 3.18 mmol), anhydrous HOBt (0.43g; 3.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.61 g; 3.18 mmol) and DIPEA (0.55 ml; 3.18 mmol) weredissolved in 5 ml of dry DCM.4-(1-(2-Aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.6 g; 2.12mmol) and DIPEA (0.55 ml; 3.18 mmol) were dissolved in 5 ml of dry DCMand added dropwise to the previous mixture. The reaction mixture wasstirred overnight after which pyrazine-2,5-dicarboxylic acid (0.27 g;1.59 mmol), anhydrous HOBt (0.52 g; 3.81 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.41 g:2.12 mmol) and DIPEA (0.37 ml; 2.12 mmol) were added to drive thereaction to completion. After 2.5 h the mixture was diluted with 20 mlof DCM. After addition of 10 ml of water, the product precipitated andwas filtered yielding 0.42 g of crude product which was used withoutfurther purification.

c)N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-5-(morpholine-4-carbonyl)pyrazine-2-carboxamide

5-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethylcarbamoyl)pyrazine-2-carboxylicacid (0.11 g; 0.29 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.083 g: 0.43 mmol), anhydrous HOBt (0.058 g; 0.43 mmol),dipea (0.075 ml; 0.43 mmol) and morpholine (0.025 g; 0.29 mmol) weredissolved in 5 ml of dry DCM and stirred overnight. The solution wasdiluted with 10 ml of DCM and washed with 3×5 ml water. The combinedwater phases were extracted with 2×5 ml DCM and the combined organicphases dried over Na₂SO₄, filtered and evaporated to dryness. Theproduct was purified using flash chromatography DCM/MeOH as gradienteluent. Yield 0.06 g. ¹H-NMR (400 MHz; d₆-DMSO): δ 3.45 (t, 2H), 3.56(t, 2H), 3.69 (s, 4H), 3.76-3.80 (m, 2H), 4.42 (t, 2H), 6.97 (d, 1H),7.87 (d, 1H), 7.94-8.01 (m, 2H), 8.01 (s, 1H), 8.93 (d, 1H), 9.13 (s,1H), 9.22-9.25 (t, 1H).

Example 36N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-3-carboxamidea) Methyl 5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-3-carboxylate

Phenylhydrazine (0.5 g; 4.62 mmol), acetylenedicarboxylic acid dimethylester (0.66 g; 4.62 mmol) and 4-toluenesulfonic acid pyridine salt (1.16g; 4.62 mmol) were dissolved in 7 ml of dry THF under nitrogenatmosphere and the solution was stirred for 2 h at RT after which 7 mlof 10% HCl (g) in EtOAc was added and the mixture heated at 67° C. for 5h. The reaction mixture evaporated to dryness and 6 ml of DCM added tothe residue. The organic phase was washed with 8 ml of water and thecombined water phases were extracted with 2×6 ml of DCM. The combinedorganic phases were once more washed with 12 ml of water, dried overNa₂SO₄, filtered and evaporated to dryness to give 0.35 g of the productwhich was used as such without further purification.

b) 5-Oxo-1-phenyl-2,5-dihydro-1H-pyrazole-3-carboxylic Acid

Methyl 5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-3-carboxylate (0.35 g;1.60 mmol) in 5 ml of 2M NaOH solution was heated at 60° C. for 2 hafter which the reaction mixture was made acidic with 1.5 ml ofconcentrated HCl which caused the product to form a yellow precipitate.Filtering gave 0.18 g of the product. ¹H-NMR (400 MHz; d₆-DMSO): δ 5.97(s, 1H), 7.33-7.37 (m, 1H), 7.48-7.52 (m, 2H), 7.74 (m, 2H).

c)N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-3-carboxamide

5-Oxo-1-phenyl-2,5-dihydro-1H-pyrazole-3-carboxylic acid (0.05 g; 0.24mmol), HOBt (0.049 g; 0.37 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.07 g;0.37 mmol) were added to 2.5 ml of DCM. To this a mixture of4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.06 g; 0.24mmol) and DIPEA (0.064 ml; 0.37 mmol) was added dropwise and the mixturewas stirred overnight after which 10 ml of DCM was added. The mixturewas washed with 3×5 ml of water and the combined water phases wereextracted with 2×5 ml of DCM. The combined organic layers were driedover Na₂SO₄, filtered and evaporated to dryness. The product waspurified with flash chromatography using DCM/MeOH as gradient eluent.The combined fractions gave 18 mg of the product. ¹H-NMR (400 MHz;d₆-DMSO): δ 1.23 (s, 1H), 3.65-3.70 (m, 2H), 4.37 (t, 2H), 5.83 (s, 1H),6.97 (d, 1H), 7.31-7.35 (t, 1H), 7.45-7.49 (t, 2H), 7.76 (d, 2H),7.85-7.89 (m, 2H), 7.94-7.96 (m, 1H), 8.09 (d, 1H), 8.28 (m, 1H).

Example 373-Methyl-N-(2-(3-(8-nitroisoquinolin-5-yl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-5-carboxamidea) 8-Nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isoquinoline

The title compound was prepared using the method of Example 34(a)starting from 0.5 g of 5-bromo-8-nitroisoquinoline. Yield 0.49 g. ¹H-NMR(400 MHz; d₆-DMSO): δ 1.43-1.51 (m, 3H), 1.80-1.89 (m, 2H), 2.32-2.33(m, 1H), 3.25-3.27 (m, 1H), 3.76-3.78 (m, 1H), 5.06 (d, 1H), 6.65 (d,1H), 6.68 (d, 1H), 7.78 (d, 1H), 8.02 (d, 1H), 8.54 (d, 1H), 8.72 (d,1H), 9.84 (s, 1H).

b) 8-Nitro-5-(1H-pyrazol-5-yl)isoquinoline

The title compound was prepared from8-nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isoquinoline(0.49 g) using the method of Example 34(b). Yield 0.35 g. ¹H-NMR (400MHz; d₆-DMSO): δ 6.92 (d, 1H), 8.00 (br s, 1H), 8.18 (d, 1H), 8.48 (d,1H), 8.75 (d, 1H), 8.87 (br s, 1H), 9.84 (s, 1H), 13.50 (br s, 1H).

c) 2-(3-(Isoquinolin-5-yl)-1H-pyrazol-1-yl)ethanamine

To 0.50 g of 8-nitro-5-(1H-pyrazol-5-yl)isoquinoline was added 5 ml ofdry DMF and the mixture was stirred at RT for 30 min. To this was added0.65 g of 2-(tert-butoxycarbonylamino)ethyl methanesulfonate diluted to1.5 ml of dry DMF and the mixture was microwaved for 30 min at 160° C.After pouring the mixture to water, it was extracted with EtOAc.Combined organic phases were washed with water and brine, dried withNa₂SO₄ and evaporated. Crude product was purified by CombiFlash (5% MeOHin DCM). Product fractions were combined and evaporated to give 0.59 gof Boc-protected product. For Boc deprotection 8 ml of 10% HCl/EtOHsolution was added to the evaporation residue, stirred at RT untildisappearance of starting material by TLC. 3 ml of diethylether wasadded to the mixture and the precipitate was filtered, washed withdiethylether and dried to give 0.30 g of the product as HCl-salt. ¹H-NMR(400 MHz; d₆-DMSO): δ 1.57 (br s, 2H), 3.04 (t, 2H), 4.25 (t, 2H), 6.90(d, 1H), 8.00 (d, 1H), 8.17 (d, 1H), 8.47 (d, 1H), 8.75 (d, 1H), 8.91(d, 1H), 9.83 (s, 1H).

d)3-Methyl-N-(2-(3-(8-nitroisoquinolin-5-yl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-5-carboxamide

The title compound was prepared from2-(3-(Isoquinolin-5-yl)-1H-pyrazol-1-yl)ethanamine (0.15 g) and3-methyl-1H-pyrazole-5-carboxylic acid (0.080 g) using the method ofExample 34(d). Yield 0.15 g. ¹H-NMR (400 MHz; d₆-DMSO): δ 2.25 (s, 3H),3.75 (t, 2H), 4.56 (t, 2H), 6.35 (s, 1H), 6.88 (d, 1H), 7.96 (d, 1H),8.16 (d, 1H), 8.21 (br s, 1H), 8.47 (d, 1H), 8.62 (d, 1H), 8.88 (d, 1H),9.82 (s, 1H), 12.90 (br s, 1H).

Example 383-(Furan-2-yl)-N-(2-(3-(2-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-5-carboxamidea) 5-(2-Methoxy-4-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

The title compound was prepared using the method of Example 34(a)starting from 2.46 g of 1-iodo-2-methoxy-4-nitrobenzene. Yield 1.88 g.¹H-NMR (400 MHz; d₆-DMSO): δ 1.41-1.63 (m, 3H), 1.80-1.87 (m, 1H),1.90-1.98 (m, 1H), 2.26-2.38 (m, 1H), 3.35-3.42 (m, 1H), 3.80-3.85 (m,1H), 3.92 (s, 3H), 5.05 (d, 1H), 6.44 (d, 1H), 7.60 (d, 1H), 7.61 (d,1H), 7.91 (d, 1H), 7.95 (d, 1H).

b) 5-(2-Methoxy-4-nitrophenyl)-1H-pyrazole

The title compound was prepared from 1.88 g of5-(2-methoxy-4-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazoleusing the method of Example 34(b). Yield 1.32 g. ¹H-NMR (400 MHz;d₆-DMSO): δ 4.02 (s, 3H), 6.90 (d, 1H), 7.82-7.86 (m, 3H), 8.21 (d, 1H),13.2 (br s, 1H).

c) 2-(3-(2-Methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethanamine

The title compound was prepared from5-(2-Methoxy-4-nitrophenyl)-1H-pyrazole (1.00 g) and2-(tert-butoxycarbonylamino)ethyl methanesulfonate (1.42 g) using themethod of Example 37(c). Yield 0.24 g (as HCl-salt). ¹H-NMR (400 MHz;d₆-DMSO): δ 3.32 (t, 2H), 4.02 (s, 3H), 4.47 (t, 2H), 6.94 (d, 1H),7.88-7.93 (m, 3H), 8.12 (br s, 2H), 8.22 (d, 1H).

d)3-(Furan-2-yl)-N-(2-(3-(2-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-5-carboxamide

The title compound was prepared from2-(3-(2-Methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethanamine (0.11 g) and3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid (0.079 g) using the methodof Example 34(d). Yield 0.11 g. ¹H-NMR (400 MHz; d₆-DMSO): δ 3.71 (t,2H), 4.01 (s, 3H), 4.39 (t, 2H), 6.57-6.68 (m, 2H), 6.85-6.89 (m, 2H),7.76-7.93 (m, 4H), 8.15-8.22 (m, 1H), 8.53 (br s, 1H), 13.71 (br s, 1H).

Example 39N-(2-(3-(3-cyano-4-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamidea) 2-Nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile

5-Chloro-2-nitrobenzonitrile (1.5 g),1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.74 g), PEPPSI ((1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)(3-chloropyridyl)palladium(ii) dichloride) (0.11 g), K₂CO₃ (2.27 g) inDMF (30 ml) and water (3 ml) was stirred under argon at 90° C. for 2.5h. After pouring the mixture to water, it was extracted with EtOAc.Combined organic phases were washed with 5% NaHCO₃, water and brine,dried with Na₂SO₄ and evaporated. The residue was triturated withethanol. The precipitate was filtered and washed with water. Yield 1.96g. ¹H-NMR (400 MHz; d₆-DMSO): δ 1.50-1.65 (m, 3H), 1.83-1.87 (m, 1H),1.95-1.99 (m, 1H), 2.33-2.42 (m, 1H), 3.60-3.67 (m, 1H), 3.95-4.00 (m,1H), 5.34 (d, 1H), 6.82 (d, 1H), 7.68 (d, 1H), 8.11 (dd, 1H), 8.32 (d,1H), 8.54 (d, 1H).

b) 2-nitro-5-(1H-pyrazol-5-yl)benzonitrile

The title compound was prepared from 1.96 g of2-nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrileusing the method of Example 34(b). Yield 1.40 g. ¹H-NMR (400 MHz;d₆-DMSO): δ 7.10 (d, 1H), 7.90 (d, 1H), 8.37 (dd, 1H), 8.43 (d, 1H),8.54 (d, 1H), 13.4 (br s, 1H).

c) 5-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile

The title compound was prepared from2-nitro-5-(1H-pyrazol-5-yl)benzonitrile (1.00 g) and2-(tert-butoxycarbonylamino)ethyl methanesulfonate (1.45 g) using themethod of Example 37(c). Yield 0.32 g (as HCl-salt). ¹H-NMR (400 MHz;d₆-DMSO): δ 3.34 (t, 2H), 4.50 (t, 2H), 7.15 (d, 1H), 7.99 (d, 1H), 8.21(br s, 2H), 8.39 (dd, 1H), 8.45 (d, 1H), 8.61 (d, 1H).

d)N-(2-(3-(3-cyano-4-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared from5-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (0.10 g) and3-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid (0.077 g) using themethod of Example 34(d). Yield 0.21 g. ¹H-NMR (400 MHz; d₆-DMSO): δ 3.75(t, 2H), 4.41 (t, 2H), 7.09 (s, 1H), 7.24-7.39 (m, 2H), 7.82-7.91 (m,3H), 8.37-8.70 (m, 5H), 13.84 (br s, 1H).

Example 40N-(2-(3-(3,4-dicyanophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamidea) 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phthalonitrile

The title compound was prepared using the method of Example 34(a)starting from 2.29 g 4-iodophthalonitrile. Yield 2.28 g. ¹H-NMR (400MHz; d₆-DMSO): δ 1.50-1.65 (m, 3H), 1.82-1.86 (m, 1H), 1.94-1.99 (m,1H), 2.32-2.41 (m, 1H), 3.58-3.64 (m, 1H), 3.94-3.97 (m, 1H), 5.33 (d,1H), 6.76 (d, 1H), 7.67 (d, 1H), 8.06 (dd, 1H), 8.29 (d, 1H), 8.31 (d,1H).

b) 4-(1H-pyrazol-5-yl)phthalonitrile

The title compound was prepared from 2.28 g of4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phthalonitrile using themethod of Example 34(b). Yield 1.53 g. ¹H-NMR (400 MHz; d₆-DMSO): δ 7.05(d, 1H), 7.91 (br s, 1H), 8.16 (d, 1H), 8.34 (dd, 1H), 8.54 (d, 1H),13.36 (br s, 1H).

c) 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)phthalonitrile

The title compound was prepared from 4-(1H-pyrazol-5-yl)phthalonitrile(0.38 g) and 2-(tert-butoxycarbonylamino)ethyl methanesulfonate (0.61 g)using the method of Example 37(c). Yield 0.050 g (as HCl-salt). ¹H-NMR(400 MHz; d₄-MeOH): δ 3.50 (t, 2H), 4.54 (t, 2H), 6.94 (d, 1H), 7.81 (d,1H), 7.98 (d, 1H), 8.28 (dd, 1H), 8.49 (d, 1H).

d)N-(2-(3-(3,4-dicyanophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared from4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)phthalonitrile (0.050 g) and3-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid (0.042 g) using themethod of Example 34(d). Yield 0.062 g. ¹H-NMR (400 MHz; d₆-DMSO): δ3.72 (t, 2H), 4.40 (t, 2H), 7.01 (s, 1H), 7.27-7.40 (m, 2H), 7.88-7.94(m, 3H), 8.14 (d, 1H), 8.32 (d, 1H), 8.35-8.65 (m, 3H), 13.9 (br s, 1H).

Example 41N-(2-(3-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-5-methyl-1H-pyrazole-3-carboxamidea) 2-(3-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethanamine

5-(3-methoxy-4-nitrophenyl)-1H-pyrazole (0.555 g, 2.53 mmol), tert-butyl2-hydroxyethylcarbamate (0.449 g, 2.79 mmol) and triphenylphosphine(0.863 g, 3.29 mmol) and THF (20 ml) were mixed. DIAD (0.997 ml, 5.06mmol) was added. The mixture was stirred for 3 h. 10% EtOH/HCl (50 ml)was added. The mixture was stirred overnight. The solvent was removed byevaporation. Water (20 ml) was added to the residue. This mixture waswashed with DCM (2×20 ml). 1 M NaOH was added until pH 14 was reachedfollowed by extraction with DCM (3×20 ml). The organic layers werepooled and evaporated to dryness. Flash chromatography (gradient ofDCM:MeOH) gave 97 mg of the title compound. ¹H-NMR (400 MHz; CDCl₃): δ3.19-3.26 (m, 2H), 4.04 (s, 3H), 4.20-4.28 (m, 2H), 6.63 (m, 1H),7.38-7.43 (m, 1H), 7.52 (m. 1H), 7.59 (m, 1H), 7.91-7.97 (m, 1H).

b)N-(2-(3-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-5-methyl-1H-pyrazole-3-carboxamide

3-Methylpyrazole-5-carboxylic acid (70.0 mg, 0.555 mmol), HOBt (85 mg,0.629 mmol) and PS-carbodiimide (672 mg) were weighed in a glass vial.DCM (4 ml) and DMF (0.4 ml) were added. The mixture was stirred for 10minutes. 2-(3-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethanamine (97mg, 0.370 mmol) was added and the mixture was stirred for 24 h. Thesolids were filtered off. PS-Trisamine (616 mg, 1.849 mmol) was added tothe filtrate. The mixture was stirred for 2 h and filtered. The filtratewas concentrated and purified by flash chromatography (gradient ofDCM:MeOH) to give 46 mg of the title compound. ¹H-NMR (400 MHz; CDCl₃):δ 2.35 (s, 3H), 3.92, (m, 2H), 4.05, (s, 3H), 4.40, (t, 2H), 6.57 (s,1H), 6.61 (d, 1H), 7.31 (s, 1H), 7.40-7.43 (m, 1H), 7.47 (d, 1H), 7.62(d, 1H), 7.96 (d, 1H), 9.94 (s, 1H).

Example 42N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide

5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml)and DMF (0.4 ml) were were mixed in a glass vial. The mixture was shakenfor 10 min. 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(49 mg, 0.20 mmol) was added and the mixture was stirred for 24 h. Thesolids were filtered off. PS-Trisamine (333 mg, 1.0 mmol) was added tothe filtrate. The mixture was shaken for 4 h and filtered. The filtratewas concentrated and purified by flash chromatography (gradient ofDCM:MeOH) to give 16 mg of the title compound. ¹H-NMR (400 MHz;d6-DMSO): 3.70 δ (m, 2H), 3.91 (s, 3H), 4.38 (m, 2H), 6.89 (m, 1H), 6.97(d, 1H), 7.85 (m, 1H), 7.94-8.00 (m, 3H), 8.10 (d, 1H), 8.36 (s, 1H),8.86-9.13 (m, 1H).

Example 43(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide

5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml)and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for10 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(51 mg, 0.2 mmol) was added and the mixture was stirred for 24 h. Thesolids were filtered off. PS-Trisamine (333 mg, 1.0 mmol) was added tothe filtrate. The mixture was shaken for 4 h and filtered. The filtratewas concentrated and purified by flash chromatography (gradient ofDCM:MeOH) to give 12 mg of the title compound. ¹H-NMR (400 MHz; CDCl₃):δ 1.25 (d, 3H), 4.00 (s, 3H), 4.23-4.31 (m, 1H), 4.42-4.48 (m, 1H),4.55-4.66 (m, 1H), 6.63 (d, 1H), 6.66 (s, 1H), 7.50 (d, 1H), 7.69 (d,1H), 7.79-7.94 (m, 4H), 8.07 (m, 1H).

Example 44(S)—N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide

5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml)and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for10 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile(48 mg, 0.2 mmol) was added and the mixture was stirred for 24 h. Thesolids were filtered off. PS-Trisamine (333 mg, 1.0 mmol) was added tothe filtrate. The mixture was shaken for 4 h and filtered. The filtratewas concentrated and purified by flash chromatography (gradient ofDCM:MeOH) to give 15 mg of the title compound. ¹H-NMR (400 MHz; CDCl₃):δ 1.25 (d, 3H), 4.00 (s, 3H), 4.23-4.28 (m, 1H), 4.42-4.49 (m, 1H),4.55-4.66 (m, 1H), 6.62 (d, 1H), 6.67 (s, 1H), 7.49 (d, 1H), 7.63 (d,1H), 7.72-7.75 (m, 1H), 7.81 (m, 2H), 7.96 (s, 1H), 8.14 (m, 1H).

Example 45N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-3-methylbutan-2-yl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamidea) 4-(1-(2-amino-3-methylbutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

The title compound was prepared using the method of Example 34(c)starting from 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (0.2 g; 0.98mmol) and tert-butyl 1-hydroxy-3-methylbutan-2-ylcarbamate (0.22 g; m1.09 mmol). Yield 22%. ¹H-NMR (400 MHz; CDCl₃): δ 1.02 (m, 6H), 1.71 (m,1H), 3.14 (m, 1H), 3.95 (m, 1H), 4.27 (m, 1H), 6.61 (d, 1H), 7.51 (d,1H), 7.66 (d, 1H), 7.77 (dd, 1H), 7.97 (s, 1H).

b)N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-3-methylbutan-2-yl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from4-(1-(2-amino-3-methylbutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(0.060 g; 0.21 mmol) and 5-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid(0.039 g; 0.21 mmol). The crude product was purified by flashchromatography using cyanocolumn and EtOAc/heptane as eluent. Yield 12%.¹H-NMR (400 MHz; MeOD): δ 1.14 (m, 6H), 1.95 (m, 1H), 4.35 (m, 2H), 4.55(m, 1H), 6.71 (s, 1H), 7.02 (m, 1H), 7.53 (m, 1H), 7.72 (m, 3H), 7.95(s, 1H), 8.25 (m, 1H), 8.54 (m, 1H), 8.88 (m, 1H).

Example 46N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

The title compound was prepared using the method of Example 34 (d)starting from pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.16 g; 0.97mmol) and 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(0.20 g; 0.81 mmol). Yield 12%. ¹H-NMR (400 MHz; d₆-DMSO): δ 3.75 (q,2H), 4.41 (t, 2H), 6.96 (d, 1H), 7.03 (s, 1H), 7.19 (m, 1H), 7.86 (d,1H), 7.97 (m, 2H), 8.06 (s, 1H), 8.64 (m, 1H), 8.71 (m, 1H), 9.09 (d,1H).

Example 47N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamidea) 2-Nitro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile

The title compound was prepared from 4-chloro-2-nitrobenzonitrile (1.50g) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1H-pyrazole(2.74 g) using the method of Example 39(a). Yield 1.75 g. ¹H-NMR (400MHz; d₆-DMSO): δ 1.57 (m, 3H), 1.84 (m, 1H), 1.97 (m, 1H), 2.38-2.47 (m,1H), 3.68-3.75 (m, 1H), 4.03 (m, 1H), 5.33 (dd, 1H), 6.84 (d, 1H), 7.69(d, 1H), 8.13 (dd, 1H), 8.31 (d, 1H), 8.60 (d, 1H).

b) 2-Nitro-4-(1H-pyrazol-5-yl)benzonitrile

The title compound was prepared from 1.53 g of2-nitro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrileusing the method of Example 34(b). Yield 1.0 g. ¹H-NMR (400 MHz;d₆-DMSO): δ 7.09 (d, 1H), 7.92 (s, 1H), 8.19 (d, 1H), 8.37 (dd, 1H),8.73 (d, 1H), 13.40 (br s, 1H).

c) 2-(tert-Butoxycarbonylamino)ethyl methanesulfonate

tert-Butyl N-(2-hydroxyethyl)carbamate (6.0 g), triethylamine (5.68 ml)were dissolved in DCM (50 ml) and methanesulfonyl chloride (3.02 ml) wasadded dropwise to the reaction mixture at 0° C. The mixture was stirredfor 30 min at 0° C. and stirring was continued for 2 h at RT. Water wasadded and the mixture was extracted with DCM. Combined organic phaseswere washed with water and brine, dried with Na₂SO₄ and evaporated. Theproduct was stored under nitrogen. Yield 8.64 g. ¹H-NMR (400 MHz;d₆-DMSO): δ 1.39 (s, 9H), 3.16 (s, 3H), 3.23 (q, 2H), 4.16 (t, 2H), 7.04(br s, 1H).

d) tert-Butyl2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethylcarbamate

2-Nitro-4-(1H-pyrazol-5-yl)benzonitrile (1.0 g), DMF (10 ml) and sodiumhydride (60% in oil, 0.24 g) were stirred for 30 min at RT.2-(tert-Butoxycarbonyl-amino)ethyl methanesulfonate (1.45 g) in DMF (3.3ml) was added and the mixture was microwaved for 30 min at 160° C.(Biotage Initiator Sixty operating at 2.45 GHz). After pouring themixture to water, it was extracted with EtOAc. Combined organic phaseswere washed with water and brine, dried with Na₂SO₄ and evaporated. Theproduct was triturated with IPA and filtered. Yield 0.92 g. ¹H-NMR (400MHz; d₆-DMSO): δ 1.35 (s, 9H), 3.38 (m, 2H), 4.24 (t, 2H), 6.92 (m, 1H),7.06 (d, 1H), 7.85 (d, 1H), 8.19 (d, 1H), 8.33 (dd, 1H), 8.70 (d, 1H).

e) 4-(1-(2-Aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile

To a solution of tert-butyl2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)-ethylcarbamate (0.92 g) inDCM (3 ml) 17% HCl-ethanol solution (10 ml) was added and the mixturewas stirred at RT until disappearance of the starting material. Theprecipitate was filtrated, washed with diethylether and dried to give0.70 g of the product as HCl-salt. ¹H-NMR (400 MHz; d₆-DMSO): δ 3.31 (m,2H), 4.50 (t, 2H), 7.12 (d, 1H), 7.99 (d, 1H), 8.19 (d, 1H), 8.27-8.35(m, 3H), 8.37 (dd, 1H), 8.73 (d, 1H).

f)N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared from4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (300 mg) and3-(pyridine-2-yl)-1H-pyrazole-5-carboxylic acid (161 mg) using themethod of Example 34(d). Yield 166 mg. ¹H-NMR (400 MHz; d6-DMSO): δ 3.75(q, 2H), 4.43 (t, 2H), 7.09 (d, 1H), 7.31 (br. s, 1H), 7.39 (m, 1H),7.88-7.96 (m, 3H), 8.20 (d, 1H), 8.37 (dd, 1H), 8.47-8.57 (m, 1H), 8.64(m, 1H), 8.71 (d, 1H), 13.90 (m, 1H).

Example 483-acetyl-N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-5-carboxamide

The title compound was prepared from4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (150 mg) and3-acetyl-1H-pyrazole-5-carboxylic acid (94 mg) using the method ofExample 34(d). Yield 84 mg. ¹H-NMR (400 MHz; d6-DMSO): δ 3.30 (s, 3H),3.71 (q, 2H), 4.39 (t, 2H), 7.05 (d, 1H), 7.27 (br. s, 1H), 7.88 (d,1H), 8.18 (d, 1H), 8.33 (d, 1H), 8.45-8.75 (m, 1H), 8.66 (d, 1H), 14.16(s, 1H).

Example 49N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-5-methylisoxazole-3-carboxamide

The title compound was prepared from4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (150 mg) and5-methylisoxazole-3-carboxylic acid (89 mg) using the method of Example34(d). Yield 9 mg. ¹H-NMR (400 MHz; d6-DMSO): δ 2.44 (s, 3H), 3.70 (q,2H), 4.40 (t, 2H), 6.48 (d, 1H), 7.05 (d, 1H), 7.88 (d, 1H), 8.18 (d,1H), 8.32 (dd, 1H), 8.67 (d, 1H), 8.79 (m, 1H).

Example 50.N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamide

The title compound was prepared from4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (50 mg) and3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (44 mg) using the methodof Example 34(d). Yield 27 mg. ¹H-NMR (400 MHz; d6-DMSO): δ 3.74 (m,2H), 4.42 (t, 2H), 7.07 (d, 1H), 7.17-7.28 (m, 1H), 7.50 (m, 1H), 7.90(s, 1H), 8.05-8.20 (m, 2H), 8.31-8.42 (m, 1H), 8.52-8.59 (m, 1H), 8.69(d, 1H), 8.92-9.04 (m, 1H), 13.79 (s, 1H).

Example 513-Acetyl-N-(2-(3-(3,4-dicyanophenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-5-carboxamide

The title compound was prepared from4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-phthalonitrile (50 mg) and3-acetyl-1H-pyrazole-5-carboxylic acid (34 mg) using the method ofExample 34(d). Yield 43 mg. ¹H-NMR (400 MHz; d6-DMSO): δ 2.49 (s, 3H),3.70 (m, 2H), 4.37 (t, 2H), 7.00 (d, 1H), 7.27 (s, 1H), 7.86 (d, 1H),8.13 (d, 1H), 8.28 (d, 1H), 8.45 (d, 1H), 8.63 (br s, 1H), 14.05 (br s,1H).

Example 52N-(2-(3-(3,4-dicyanophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared from4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-phthalonitrile (50 mg) and3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (42 mg) using the methodof Example 34(d). Yield 39 mg. ¹H-NMR (400 MHz; d6-DMSO): δ 3.73 (q,2H), 4.40 (t, 2H), 7.02 (d, 1H), 7.21 (s, 1H), 7.49 (m, 1H), 7.88 (s,1H), 8.11-8.16 (m, 2H), 8.30 (dd, 1H), 8.40-8.58 (m, 1H), 8.48 (d, 1H),8.56 (d, 1H), 8.99 (s, 1H), 13.78 (br s, 1H).

Example 53N-(2-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 31 using5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.46 g; 2.43 mmol),4-(1-(2-amino-ethyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (0.50 g; 2.21mmol), HOBt (0.45 g; 3.31 mmol), EDCI (0.64 g; 3.31 mmol) and 0.58 ml(3.31 mmol) of DIPEA as starting materials. After workup the product wasprecipitated out from DCM to give 0.56 g (64%) of the title compound.¹H-NMR (400 MHz; d6-DMSO): δ 3.67-3.76 (m, 2H), 4.33-4.41 (m, 2H), 6.85(d, 1H), 7.22 (s, 1H), 7.49 (dd, 1H), 7.74-7.82 (m, 2H), 7.83 (d, 1H),7.88 (broad s, 1H), 8.10-8.18 (m, 1H), 8.44-8.58 (m, 2H), 9.00 (broad s,1H), 13.82 (s, 1H).

Example 543-Acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-5-carboxamide

3-Acetyl-1H-pyrazole-5-carboxylic acid (0.469 g; 3.04 mmol) and 0.8 mlof DIPEA were dissolved in 3 ml of dry DCM under nitrogen. HOBt (0.616g; 4.56 mmol) and EDCI (0.874 g; 4.56 mmol) were added.4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.75 g; 3.04mmol) was added in 4.5 ml of DCM and stirred overnight at RT. 60 ml ofDCM was added and washed with 3×17 ml of water. Combined water phaseswere washed with 2×30 ml of DCM. All DCM washes were combined and driedover Na₂SO₄, filtered and evaporated. Product was purified bytrituration in 2 ml of EtOH to give the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 2.49 (s, 3H), 3.70 (m, 2H), 4.37 (m, 2H), 6.95 (d, 1H), 7.28(s, 1H), 7.84 (d, 1H), 7.94, (dd, 1H), 7.98 (d, 1H), 8.07 (d, 1H), 8.64(broad s, 1H), 14.19 (s, 1H).

Example 55(R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamidea) (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

The title compound was prepared with the Mitsunobu reaction using themethod of Example 3(c) starting from2-chloro-4-(1H-pyrazol-5-yl)-benzonitrile (2.00 g, 9.82 mmol) and(R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.893 g, 10.80 mmol).After Boc removal and workups 0.434 g (17%) of the title compound wasobtained. ¹H-NMR (400 MHz; d6-DMSO): δ 0.97 (d, 3H), 2.96 (m, 2H), 4.15(m, 2H), 6.98 (d, 1H), 7.86 (d, 1H), 7.92-8.00 (m, 2H), 8.11 (d, 1H).

b)(R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 34(d).(R)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.00 g,3.84 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.591 g; 3.84 mmol),1.0 ml of DIPEA were dissolved in 3 ml of dry DCM under nitrogen. HOBt(0.777 g; 5.75 mmol) and EDCI (1.103 g; 5.75 mmol) were added and thereaction stirred at RT overnight. The crude product (576 mg) wascrystallized from 4 ml of EtOH to obtain 164 mg (11%) of the titlecompound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.49 (s, 3H),4.34-4.38 (m, 2H), 4.40-4.53 (m, 1H), 6.93 (d, 1H), 7.31 (m, 1H), 7.81(d, 1H), 7.85-8.09 (m, 3H), 8.48 (broad s, 1H), 14.15 (s, 1H).

Example 56N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide(100 mg; 0.25 mmol) and 5 ml of EtOH were put to reaction flask andsodium borohydride (19 mg; 0.5 mmol) was added slowly as EtOHsuspension. The reaction was stirred overnight to completion. 0.5 ml ofwater and 1 ml of 0.5M HCl were added dropwise. The solution wasevaporated to dryness, 20 ml of DCM was added and washed with 10 ml of 1M NaHCO₃ and 10 ml of water followed with drying over Na₂SO₄. Afterfiltration and evaporation 76 mg (76%) of pure title compound wasobtained. 1H-NMR (400 MHz; d6-DMSO): δ 1.11 (d, 3H), 1.38 (d, 3H),4.22-4.48 (m, 3H), 4.74-4.84 (m, 1H), 4.41 (d, 1H), 6.40 (s, 1H), 6.94(d, 1H), 7.81 (d, 1H), 7.92-8.05 (m, 2H), 8.09 (d, 1H), 8.20 (d, 1H),13.04 (s, 1H).

Example 57(S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

The compound was prepared using the method of Example 34(d).(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.00 g;3.84 mmol), 2-aminothiazole-4-carboxylic acid (0.66 g; 4.66 mmol), 1.00ml of DIPEA, HOBt (0.26 g; 1.9 mmol) and EDCI (1.10 g; 5.75 mmol) wereused as starting materials. Purification by isopropanol:toluenecrystallization afforded 0.93 g (63%) of the title compound. ¹H-NMR (400MHz; d6-DMSO): δ 1.10 (d, 3H), 4.22-4.45 (m, 3H), 6.96 (d, 1H), 7.04(broad s, 2H), 7.15 (s, 1H), 7.82 (d, 1H), 7.90 (d, 1H), 7.97 (s, 1H),8.08 (s, 1H).

Example 58(R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamidea) (R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrilehydrochloride

The Mitsunobu reaction was conducted as described in Example 3(c) using2-chloro-4-(1H-pyrazol-5-yl)benzonitrile (0.60 g, 2.95 mmol) and(R)-tert-butyl 1-hydroxybutan-2-ylcarbamate (0.61 g, 3.24 mmol) asstarting materials. 0.249 g (31%) of the title compound was obtainedafter workup. ¹H-NMR (400 MHz; d6-DMSO): δ 0.91 (t, 3H), 1.22 (d, 3H),3.33 (broad s, NH₂HCl overlapping with water) 3.99 (dd, 1H), 4.12 (dd,1H), 4.44-4.86 (m, 1H), 6.97 (d, 1H), 7.86 (d, 1H), 7.92-7.99 (m, 2H),8.11 (d, 1H).

b)(R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamide

The compound was prepared using the method of Example 34(d). Thereaction was conducted in 4 ml of DCM at RT overnight using(R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.249 g;0.91 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.140 g; 0.91 mmol),0.24 ml of DIPEA, HOBt (0.184 g; 1.36 mmol) and EDCI (0.261 g; 1.36mmol) as starting materials. Purification was done by EtOH trituration.¹H-NMR (400 MHz; d6-DMSO): δ 0.90 (t, 3H), 1.42-1.67 (m, 2H), 2.51 (s,3H), 4.19-4.42 (m, 3H), 6.91 (d, 1H), 7.32 (s, 1H), 7.79 (d, 1H),7.85-8.07 (m, 3H), 8.38 (d, 1H), 14.14 (s, 1H).

Example 59(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

The title compound was prepared using the method of Example 54 butstarting from 1,3-thiazole-4-carboxylic acid (149 mg; 1.51 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (300 mg;1.51 mmol). Crude product was purified by EtOH trituration to obtain 84mg (20%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.12 (d,3H), 4.30-4.53 (m, 3H), 6.95 (d, 1H), 7.86 (d, 1H), 7.95-8.04 (m, 2H),8.15 (s, 1H), 8.28 (d, 1H), 8.77 (d, 1H), 9.23 (d, 1H).

Example 60(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(4-methylpiperazine-1-carbonyl)-1H-pyrazole-5-carboxamidea)(S)-5-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)-1H-pyrazole-3-carboxylicAcid

The title compound was prepared using the method of Example 54 butstarting from 3,5-pyrazoledicarboxylic acid monohydrate (0.60 g; 3.84mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(1.0 g; 3.84 mmol). Crude product was purified by chromatography(CombiFlash, silica column, eluent: 0-100% MeOH/DCM) to obtain 29 mg(36%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.14 (s, 3H),4.30-4.50 (m, 3H), 6.93 (d, 1H), 7.83 (s, 1H), 7.85-8.05 (m, 2H), 8.04(s, 1H), 8.35-8.65 (m, 1H), 14.06 (s, 1H), 14.24 (s, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(4-methylpiperazine-1-carbonyl)-1H-pyrazole-5-carboxamide

1-Methylpiperazine (126 mg; 1.25 mmol) and(S)-5-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-pyrazole-3-carboxylicacid (50 mg; 1.25 mmol), HOBt (254 mg; 1.88 mmol), DIPEA (0.33 ml; 1.88mmol) and EDCI (361 mg; 1.88 mmol) were dissolved in 15 ml of DCM andstirred at RT overnight. 50 ml of DCM was added and washed with 3×15 mlof water. Combined water phases were washed with 2×20 mol of DCM, allorganic phases were combined and dried over Na₂SO₄. Crude product waspurified by chromatography (CombiFlash, silica column, eluent: 0-20%MeOH/DCM) to obtain 75 mg (12%) of the title compound. ¹H-NMR (400 MHz;d1-CDCl3): δ 3.90-3.96 (m, 2H), 4.41 (t, 2H), 6.51-6.53 (m, 1H), 6.61(d, 1H), 6.66 (d, 1H), 6.95 (s, 1H), 7.48-7.50 (m, 2H), 7.61 (broad s,1H), 7.68 (d, 1H), 7.76-7.79 (m, 1H), 8.11 (s, 1H), 10.45 (broad s, 1H).

Example 61(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 54 butstarting from 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (181 mg; 0.96mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(250 mg; 0.96 mmol). The product precipitated out from DCM during workupand after filtration and drying 110 mg (27%) of pure title compound wasobtained. ¹H-NMR (400 MHz; d6-DMSO): δ 1.17 (s, 3H), 4.20-4.60 (m, 3H),7.05-7.36 (m, 1H), 7.40-7.65 (m, 1H), 7.80-8.60 (m, 7H), 8.85-9.07 (m,1H), 13.76 (s, 1H).

Example 62(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

The title compound was prepared using the method of Example 54 butstarting from thiazole-4-carboxylic acid (50 mg; 0.38 mmol) and(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg;0.38 mmol). Crude product was purified by chromatography (CombiFlash,silica C18 column, eluent: 0-100% ACN/water) to obtain 63 mg (44%) ofthe title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.12 (d, 3H), 4.30-4.52(m, 3H), 6.95 (d, 1H), 7.85 (d, 1H), 7.95-8.04 (m, 2H), 8.14 (s, 1H),8.27 (d, 1H), 8.77 (d, 1H), 9.22 (d, 1H).

Example 63N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamidea) 2-(1-hydroxy-2-methylpropan-2-yl)isoindoline-1,3-dione

2-Amino-2-methyl-1-propanol (4.46 g, 50 mmol) and phthalic anhydride(7.41 g, 50 mmol) were heated at 170° C. for 30 minutes. Icewater wasadded to the cooled reaction mixture and then the mixture was extractedthree times with DCM. Organic phase was dried over Na₂SO₄, filtered andevaporated to dryness. Crude product was purified by CombiFlash (column:silica, eluent: 0-10% MeOH in DCM) to obtain 3.611 g (33%) of the titlecompound. LC-MS: M+1=220.

b)4-(1-(2-(1,3-dioxoisoindolin-2-yl)-2-methylpropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile

2-(1-hydroxy-2-methylpropan-2-yl)isoindoline-1,3-dione (1.10 g; 5 mmol)and 2-methyl-4-(1H-pyrazol-3-yl)benzonitrile (0.366 g; 2.0 mmol) weredissolved in 5 ml of THF under nitrogen atmosphere. Triphenylphosphine(1.05 g; 4.0 mmol) and DIAD (0.79 ml; 4.0 mmol) were added and thereaction stirred at RT over the weekend. Additional triphenylphosphine(0.525 g; 2.0 mmol) and DIAD (0.39 ml; 2.0 mmol) were added and themixture was stirred at RT for 2 days and then refluxed for 2 hours.Solvent was evaporated, 50 ml of water was added and the mixture waswashed with 3×50 ml of DCM, dried over Na₂SO₄, filtered and evaporatedto dryness. The crude mixture was purified twice by CombiFlash (column:silica, eluent 0-100% EtOAc in heptane) to obtain 125 mg (16%) of thetitle product. ¹H-NMR (400 MHz; CDCl₃): δ 1.56 (s, 6H), 2.60 (s, 3H),4.2-4.38 (m, 2H), 6.50 (d, 1H), 7.33-7.87 (m, 8H).

c) 4-(1-(2-amino-2-methylpropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile

4-(1-(2-(1,3-dioxoisoindolin-2-yl)-2-methylpropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile(0.125 g; 0.33 mmol) and hydrazine hydrate (65%) (0.16 ml; 3.3 mmol)were agitated in 2 ml of EtOH and refluxed for 30 min and then for 2days at RT. Solvent was evaporated, 5 ml of water added and the mixturewas washed with 3×10 ml of 2% MeOH/DCM, dried over Na₂SO₄, filtered andevaporated to dryness. The reaction was uncomplete and the same amountsof reagents were loaded and 5 drops of DMF. The reaction was refluxedwithout progress and re-extracted like previously to obtain 80 mg of theproduct mixture containing 21% of the title compound based on LC-MSanalysis.

d)N-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 54 butstarting from 5-(2-furyl)-4H-pyrazole-3-carboxylic acid (56 mg; 0.32mmol) and4-(1-(2-amino-2-methylpropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (80mg; 0.32 mmol). Crude product was purified by chromatography(CombiFlash, silica-C18 column, eluent: 0-100% ACN/water) to obtain 16mg of the product which was further purified by preparative HPLC (WatersDeltaprep 4000, SymmPrep 56.2, 25-80% ACN/AcONH₄) to obtain 5.3 mg ofthe title compound. ¹H-NMR (400 MHz; d1-CDCl3): δ 1.52 (s, 6H), 2.54 (s,3H), 4.50 (s, 2H), 6.52 (dd, 1H), 6.57 (d, 1H), 6.64 (d, 1H), 6.90 (s,1H), 7.44 (d, 1H), 7.48 (d, 1H), 7.59 (d, 1H), 7.70 (dd, 1H), 7.75 (d,1H), 10.31 (broad s, 1H).

Example 64N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 54 butstarting from 5-(2-furyl)-4H-pyrazole-3-carboxylic acid (36 mg; 0.20mmol) and 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (50mg; 0.20 mmol). Crude product was purified by chromatography(CombiFlash, silica column, eluent: 0-100% MeOH/DCM) to obtain 29 mg(36%) of the title compound. ¹H-NMR (400 MHz; d1-CDCl3): δ 3.90-3.96 (m,2H), 4.41 (t, 2H), 6.51-6.53 (m, 1H), 6.61 (d, 1H), 6.66 (d, 1H), 6.95(s, 1H), 7.48-7.50 (m, 2H), 7.61 (broad s, 1H), 7.68 (d, 1H), 7.76-7.79(m, 1H), 8.11 (s, 1H), 10.45 (broad s, 1H).

Example 65N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 53 butstarting from 5-pyridin-2-yl-4H-pyrazole-3-carboxylic acid (38 mg; 0.20mmol) and 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (50mg; 0.20 mmol). Crude product was purified by chromatography(CombiFlash, silica column, eluent: 0-100% MeOH/DCM) to obtain 19 mg(23%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 3.70-3.74 (m,2H), 4.38 (t, 2H), 6.96 (d, 1H), 7.23-7.40 (m, 2H), 7.82-8.02 (m, 5H),8.09 (s, 1H), 8.48, (broad s, 1H), 8.62 (d, 1H), 13.89 (broad s, 1H).

Example 663-acetyl-N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 20 butstarting from 3-acetyl-1H-pyrazole-5-carboxylic acid (215 mg; 1.37 mmol)and 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine hydrochloride (400mg; 1.37 mmol). Crude product was purified by chromatography(CombiFlash, silica column, eluent: 0-100% EtOAc/heptane) to obtain 267mg (50%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 2.50 (s,3H—overlapping with DMSO), 2.93 (t, 2H), 3.54-3.60 (m, 2H), 6.33 (d,1H), 7.02 (d, 1H), 7.30 (s, 1H), 7.58-7.64 (m, 2H), 7.82 (d, 1H), 8.65(broad s, 1H), 14.21 (s, 1H).

Example 67(E/Z)—N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-(1-(hydroxyimino)ethyl)-1H-pyrazole-5-carboxamide

3-Acetyl-N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide(40 mg; 0.10 mmol) was dissolved in 5 ml of EtOH. Anhydrous NaAc (10 mg;0.12 mmol) and hydroxylamine hydrochloride (8.5 mg; 0.12 mmol) wasadded. The reaction mixture was stirred at RT for 3 days until complete.The reaction mixture was evaporated to dryness and dissolved in 10 ml ofEtOAc and washed 2×2 ml of water. After Na₂SO₄ drying and evaporation 34mg (82%) of the title compound was obtained as a mixture of E and Zisomers (1H-NMR/˜1:1). ¹H-NMR (400 MHz; d1-CDCl₃): δ 2.23/2.26 (s, 3H),2.98-3.05 (m, 2H), 3.72-3.82 (m, 2H), 6.19-6.32 (m, 1H), 6.57-6.62 (m,1H), 7.01 (d, 1H), 7.00/7.05 (s, 1H), 7.20-7.45 (m, 5H), 7.80/7.86 (t,1H), 13.86 (s, 1H).

Example 68N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-(1-(2-hydroxyethylamino)ethyl)-1H-pyrazole-5-carboxamide

3-Acetyl-N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide(78 mg; 0.20 mmol) and 2-aminoethanol (10 mg; 0.17 mmol) were dissolvedin 5 ml of dry toluene and 5 ml of dry THF and stirred for 6.5 h at 75°C. under nitrogen atmosphere and then overnight at RT. Sodiumtetrahydroborate (18.8 mg; 0.50 mmol) was added, stirred for 3 days atRT and then 4.5 h at 75° C. 10 mg of sodium tetrahydroborate was addedand the mixture was heated for 5 h at 50° C. to complete the reaction.0.1 ml of water was added at 0° C. and pH adjusted to 1 with 1 M HCl.Solution was evaporated to dryness, 15 ml of DCM was added and themixture was washed with 10 ml of water. pH was adjusted to 12 with 1 MNaOH and 15 ml of DCM was added. After Na₂SO₄ drying the compound waspurified by chromatography (CombiFlash, Silica column, 2.5-10% MeOH/DCM)to obtain 19 mg (26%) of the title compound. ¹H-NMR (400 MHz; d1-CDCl₃):δ 1.43 (d, 3H), 2.55-2.70 (m, 1H), 2.74-2.85 (m, 1H), 2.97 (t, 2H),3.60-3.76 (m, 4H), 4.02-4.12 (m, 1H), 6.16 (d, 1H), 6.53 (d, 1H), 6.65(s, 1H), 7.33-7.41 (m, 3H), 7.67 (d, 1H).

Example 69N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

The title compound was isolated as a side product in the preparation ofN-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-3-(1-(2-hydroxyethylamino)ethyl)-1H-pyrazole-5-carboxamideby a direct reduction of staring material3-acetyl-N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide.After chromatographic purification (CombiFlash, Silica column, 2.5-10%MeOH/DCM) 21 mg (32%) of the title compound was obtained. ¹H-NMR (400MHz; d6-DMSO): δ 1.38 (d, 3H), 2.93 (t, 2H), 3.54 (q, 2H), 4.70-4.85 (m,1H), 5.42 (s, 1H), 6.33 (d, 1H), 6.43 (s, 1H), 7.02 (d, 1H), 7.55-7.68(m, 2H), 7.87 (d, 1H), 8.19 (broad s, 1H), 13.03 (s, 1H).

Example 70N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

The title compound was prepared using the method of Example 20 butstarting from pyrazolo[1,5-a]pyrimidinecarboxylic acid (82 mg; 0.5 mmol)and 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine hydrochloride (146mg; 0.5 mmol). Crude product was purified by chromatography (CombiFlash,silica column, eluent: 0-20% DCM/MeOH) to obtain 107 mg of the titlecompound. The product was further purified by trituration in toluene togive 55 mg of pure product (27%). ¹H-NMR (400 MHz; d1-CDCl₃): δ 3.06 (t,2H), 3.83 (m, 2H), 6.233 (d, 1H), 6.61 (d, 1H), 6.93 (dd, 1H), 7.35-7.41(m, 2H), 7.44 (dd, 1H), 7.70 (d, 1H), 8.55 (dd, 1H), 8.57-8.60 (m, 1H).

Example 71N-(2-(3-(5-chloro-6-cyanopyridin-3-yl)-1H-pyrazol-1-yl)ethyl)-5-(pyrin-3-yl)-1H-pyrazole-3-carboxamidea) 3-amino-5-bromopicolinonitrile

Iron powder (5.0 g, 90 mmol) was added to a solution5-bromo-3-nitropyridine-2-carbonitrile (4.56 g, 20 mmol) in glacialacetic acid (125 ml). The suspension was stirred for 2 h at 80° C. Thecooled mixture was filtered through a short plug of Celite and washedwith EtOAc. Solvents were evaporated, the residue was dissolved in EtOAcand neutralised with 20% aqueous K₂CO₃. Phases were separated andorganic phase was washed with water and brine, dried over anhydrousNa₂SO₄, filtered and evaporated. Crude product was purified byCombiFlash (DCM-MeOH, gradient elution). Product fractions were combinedand evaporated to produce 1.67 g of product. ¹H-NMR (400 MHz; d6-DMSO):δ 6.55 (s, 2H), 7.46 (d, 1H, J=2.0 Hz), 7.94 (d, 1H, J=1.9 Hz).

b) 5-bromo-3-chloropicolinonitrile

Sodium nitrite (0.7 g, 10.15 mmol) was added to a cooled suspension of3-amino-5-bromopicolinonitrile (1.67 g, 8.43 g) in 37% hydrochloric acid(14 ml, 169 mmol) and water (4.5 ml) and stirred for 1 h at 0-5° C.Copper powder (0.134 g, 2.11 mmol) was added and the mixture refluxedfor 1 h. The mixture was cooled, quenched with ice water and basifiedwith 48% NaOH. The mixture was extracted with EtOAc. The organic phasewas washed with water and brine, dried over anhydrous Na₂SO₄, filteredand evaporated to give 1.21 g of the product. ¹H-NMR (400 MHz; d6-DMSO):δ 8.75 (d, 1H, J=1.9 Hz), 8.90 (d, 1H, J=1.9 Hz).

c)3-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinonitrile

5-bromo3-chloropiconilonitrile (1.68 g, 7.73 mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1-H-pyrazole(2.47 g, 8.88 mmol) were dissolved in ethylene glycol dimethyl ether (25ml) under nitrogen atmosphere. Bis(triphenylphosphine)palladium chloride(0.38 g, 0.541 mmol) and 2 M Na₂CO₃ (7.73 ml, 15.45 ml) were added andthe mixture was stirred under nitrogen atmosphere at 80° C. for 3.5 h.Solvents were evaporated and the residue was treated with water andextracted with EtOAc. The organic phase was washed with water and brine,dried over anhydrous Na₂SO₄, filtered and evaporated. Crude product waspurified by trituration with EtOAc to give 1.11 g of the product. ¹H-NMR(400 MHz; d6-DMSO): δ 1.52-1.63 (m, 3H), 1.86 (m, 1H), 1.96 (m, 1H),2.35 (m, 1H), 3.60 (m, 1H), 3.94 (m, 1H), 5.39 (dd, 1H), 6.84 (d, 1H),7.69 (d, 1H), 8.39 (d, 1H), 8.87 (d, 1H).

d) 3-chloro-5-(1H-pyrazol-5-yl)picolinonitrile

4 M hydrogen chloride in dioxane (1.1 ml, 4.40 mmol) was added to asolution of3-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinonitrile(1.1 g, 3.81 mmol) in absolute ethanol (15 ml) and stirred at RT for 3h. Solvents were evaporated and water was added to the residue. Themixture was neutralised with saturated NaHCO₃ and extracted with EtOAc.The organic phase was dried over anhydrous Na₂SO₄, filtered andevaporated to give 0.796 g of the product. ¹H-NMR (400 MHz; d6-DMSO): δ7.10 (d, 1H), 7.92 (d, 1H), 8.58 (d, 1H), 9.17 (d, 1H), 13.4 (bs, 1H).

e) 3-chloro-5-(1-(2-tritylamino)ethyl)1-H-pyrazol-3-yl)pivolinonitrile

3-chloro-5-(1H-pyrazol-5-yl)picolinonitrile (0.34 g, 1.662 mmol) wasadded to a cooled (0-5° C.) suspension of 60% sodium hydride in mineraloil (0.116 g, 2.91 mmol, washed with heptane) in dry DMF (8 ml) andstirred at RT for 1 h. The mixture was cooled to 0-5° C. and a solutionof 2-bromo-N-tritylethanamine (1.00 g, 2.73 mmol, prepared as in EP435749) in dry DMF (4 ml) was gradually added and stirred at RT for 3 h.The mixture was filtered, water and EtOAc were added to the filtrate andphases were separated. The water phase was extracted with EtOAc, organicphases were washed with water and brine, dried over anhydrous Na₂SO₄,filtered and evaporated. Crude product was purified by trituration withheptane-EtOAc to give 0.56 g of the product. ¹H-NMR (400 MHz; d6-DMSO):δ 2.38 (m, 2H), 2.97 (t, 1H), 4.29 (t, 2H), 7.1-7.3 (m, 16H), 7.98 (d,1H), 8.53 (d, 1H), 9.13 (d, 1H).

f) 5-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-3-chloropiconilonitrile

TFA (3.0 ml, 40.4 mmol) was added to a cooled solution of3-chloro-5-(1-(2-tritylamino)ethyl)1-H-pyrazol-3-yl)pivolinonitrile(0.475 g, 0.969 mmol) in DCM-MeOH (1:1, 6 ml). The mixture was stirredat RT for 48 h after which solvents were evaporated. Water and etherwere added and the phases were separated. The aqueous phase was basifiedwith 2M NaOH and extracted with DCM. Combined organic phases were driedover anhydrous Na₂SO₄, filtered and evaporated to give 0.187 g ofproduct. ¹H-NMR (400 MHz; d6-DMSO): δ 2.97 (t, 2H), 4.17 (t, 2H), 7.07(d, 1H), 7.91 (d, 1H), 8.54 (d, 1H), 9.13 (d, 1H).

g)N-(2-(3-(5-chloro-6-cyanopyridin-3-yl)-1H-pyrazol-1-yl)ethyl)-5-(pyrin-3-yl)-1H-pyrazole-3-carboxamide

HOBt hydrate (67 mg, 0.437 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg,0.436 mmol) and DIPEA (0.19 ml, 1.09 mmol) were added to a solution of5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid in DCM (6 ml) and stirredat RT for 15 min.5-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-3-chloropiconilonitrile was addedand stirring continued overnight. Solvent was evaporated, water wasadded and extracted with EtOAc. The organic phase was washed with brine,dried over anhydrous Na₂SO₄, filtered and evaporated to give 94 mg ofthe product. ¹H-NMR (400 MHz; d6-DMSO): δ 3.73 (q, 2H), 4.41 (t, 2H),7.07 (d, 1H), 7.21 (d, 1H), 7.49 (dd, 1H), 7.91 (d, 1H), 8.13 (bs, 1H),8.52 (d, 1H), 8.55 (dd, 1H), 8.99 (bs, 1H), 9.13 (d, 1H), 13.8 (bs, 1H).

Example 723-Tert-butyl-N-(1-(5-(4-cyano-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-yl)-1H-pyrazole-5-carboxamidea)(E)-2-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-nitroprop-1-enyl)furan

5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-carbaldehyde (4.00 g, 14.5mmol), nitroethane (3.00 ml, 40.7 mmol), n-butylamine (1.7 ml, 17.5mmol) and acetic acid (7.5 ml) were mixed and heated up to 80° C. for 2h. After cooling to RT the mixture was filtered. The precipitate wascrystallized from ethanol affording 2.58 g of the title product. ¹H-NMR(400 MHz; d6-DMSO): δ 2.62 (s, 3H), 7.39 (d, 1H), 7.57 (d, 1H), 7.87 (m,1H), 8.00 (s, 1H), 8.11 (m, 1H), 8.22 (m, 1H).

b) 1-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-amine

(E)-2-(4-chloro-3-(trifluoromethyl)phenyl)-5-(2-nitroprop-1-enyl)furan(2.58 g, 7.78 mmol) was mixed with diethyl ether (54 ml) and toluene (25ml) and added drop wise to a cooled (−20° C.) solution of lithiumaluminium hydride (2.5 g, 65.9 mmol) in diethyl ether (11 ml). Themixture was allowed to warm up to 0° C. and stirred for 3 h and then atRT for additional 1 h stirring. Then the mixture was cooled again and2.5 ml of water was added at −30° C. and then 2.5 ml of 15% aqueous NaOHsolution. An additional 7.5 ml of water was added and the solution wasallowed to warm to RT. MgSO₄ was added and the mixture was stirred andfiltered, precipitate was washed with toluene and diethyl ether and thefiltrate was evaporated to dryness. After CombiFlash purification withDCM:MeOH as eluent system, the pooled fractions afforded 1.13 g of thetitle compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.01 (d, 3H), 2.63 (m, 2H),3.11-3.15 (m, 1H) 6.28 (d, 1H), 7.07 (d, 1H), 7.68 (d, 1H), 7.87 (m,1H), 7.95 (m, 1H).

c)3-tert-butyl-N-(1-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

3-tert-butyl-N-(1-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-yl)-1H-pyrazole-5-carboxamidewas prepared from1-(5-(4-chloro-3-(trifluoromethyl)-phenyl)furan-2-yl)propan-2-amine(0.500 g, 1.651 mmol), 3-tert-butyl-1H-pyrazole-5-carboxylic acid (0.306g, 1.817 mmol), HOBt (0.246 g, 1.817 mmol), DIPEA (0.576 ml, 3.303 mmol)and EDCI (0.349 g, 1.817 mmol) using the method of Example 1(d)producing 0.692 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ1.19 (d, 3H), 1.26 (s, 9H), 2.87-2.92 (m, 1H), 2.96-3.00 (m, 1H),4.29-4.37 (m, 1H), 6.29-6.32 (m, 1H), 7.04-7.10 (m, 1H), 7.57-7.73 (m,1H), 7.88-7.98 (m, 3H), 12.84 (m, 1H).

d)3-tert-butyl-N-(1-(5-(4-cyano-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

3-tert-butyl-N-(1-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-yl)-1H-pyrazole-5-carboxamide(0.615 g, 1.355 mmol) was weighed into a reaction vial (Biotage) and11.6 ml of DMF was added. Zinc cyanide (0.350 g, 2.981 mmol), S-Phos(0.112 g, 0.271 mmol) and Pd₂(dba)₃ (0.100 g, 0.108 mmol) were added.The reaction vial was flushed with nitrogen, capped and heated for 30min at 150° C. in microwave oven. The mixture was allowed to cool to RTand 30 ml of 1 M NaOH was added. The mixture was extracted with EtOAcfor three times and the combined organic layers were washed with water,dried with Na₂SO₄, filtered and evaporated to dryness. CombiFlashpurification afforded 0.094 g of the title product. ¹H-NMR (400 MHz;CDCl₃): δ 1.29 (d, 3H), 1.33 (s, 9H), 3.00 (d, 2H), 4.49-4.56 (m, 1H),6.31 (d, 1H), 6.58 (s, 1H), 6.84 (d, 1H), 7.11 (m, 1H), 7.78 (m, 1H),7.85 (m, 1H), 7.95 (m, 1H).

Example 73(E)-N-(2-(5-(4-cyano-3-(trifluoromethyl)phenyl)furan-2-yl)vinyl)picolinamidea) (E)-3-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)acrylic Acid

5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-carbaldehyde (3.32 g, 13.4mmol) was dissolved in pyridine (16.6 ml) and piperidine (0.66 ml) wasadded. Malonic acid (1.67 g, 1.61 mmol) was added and the reactionmixture was refluxed for 4 h. Cooled reaction mixture was poured into asolution of ice (100 ml) water (100 ml) and conc. HCl (100 ml). Theprecipitate was filtered and washed with cold water and recrystallisedfrom ethanol to afford 2.55 g of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 6.44 (d, 1H), 7.08 (d, 1H), 7.40 (m, 1H), 7.43 (d, 1H), 7.81(d, 1H), 8.14 (m, 1H), 8.21 (m, 1H), 12.44 (m, 1H).

b) (E)-2-(2-bromovinyl)-5-(4-chloro-3-(trifluoromethyl)phenyl)furan

(E)-3-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)acrylic acid(2.55 g, 8.06 mmol) was added to a stirred solution of Dess-Martinperiodinane (18.40 ml, 59.07 mmol) and TEAB (1.84 g, 8.86 mmol) in 12.1ml of dry DCM. After 1.5 h of stirring at RT, the reaction mixture wasdiluted with DCM (60 ml) and extracted two times with sodium bisulfite(aq. 10%) solution, two times with saturated aqueous NaHCO₃ solution,two times with water and finally once with brine. Organic layer wasdried with Na₂SO₄, filtered and evaporated to dryness affording 2.44 gof the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 6.43 (d, 1H), 7.08(d, 1H), 7.67 (m, 2H), 7.93 (m, 1H), 8.17 (m, 2H).

c)(E)-N-(2-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)vinyl)picolinamide

(E)-2-(2-bromovinyl)-5-(4-chloro-3-(trifluoromethyl)phenyl)furan (0.501g, 1.378 mmol) in toluene (2.4 ml) was added to a mixture of copper(I)iodide (0.014 g, 0.069 mmol), potassium carbonate (0.381 g, 2.756 mmol),picolinamide (0.202 g, 1.654 mmol) and N,N′-dimethylethylene diamine(0.0149 ml, 0.0138 mmol) under nitrogen. The reaction mixture wasrefluxed for 7.5 h and allowed to cool to RT. It was then filtratedthrough a layer of silica and the filter cake was washed with EtOAc. Thefiltrate was evaporated to dryness and purified with CombiFlash usingheptane-DCM as eluent system affording 0.046 g of the title compound.¹H-NMR (400 MHz; d6-DMSO): δ 6.54 (d, 1H), 6.70 (d, 1H), 7.26 (d, 1H),7.61-7.70 (m, 2H), 7.77 (d, 1H), 7.99-8.02 (m, 1H), 8.04-8.09 (m, 2H),8.13 (m, 1H), 8.74 (m, 1H), 11.20 (d, 1H).

d)(E)-N-(2-(5-(4-cyano-3-(trifluoromethyl)phenyl)furan-2-yl)vinyl)picolinamide

(E)-N-(2-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)vinyl)picolinamide(0.046 g, 0.012 mmol) was treated with zinc cyanide (0.041 g, 0.026mmol), S-Phos (0.010 g, 0.002 mmol) and Pd₂(dba)₃ (0.009 g, 0.001 mmol)using the method of Example 72(d). Preparative TLC-purification afforded0.011 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 6.63 (d,1H), 6.73 (d, 1H), 7.52 (d, 1H), 7.68-7.76 (m, 2H), 8.05-8.21 (m, 5H),8.75 (d, 1H), 11.26 (d, 1H).

Example 743-tert-butyl-N-(2-(5-(3-chloro-4-cyano-2-methylphenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamidea) 3-tert-butyl-N-(2-(furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide

2-(furan-2-yl)ethanamine (0.81 g, 7.30 mmol) was added to a premixed (10min) solution of 3-tert-butyl-1H-pyrazole-5-carboxylic acid (0.61 g,3.60 mmol), DCC (1.51 g, 7.30 mmol) and HOBt (0.99 g, 7.30 mmol) inDCM:DMF-solution (10 ml, 2:9, v/v). After stirring for 15 h at RT thereaction mixture was filtered through a pad of Celite and the filtratewas washed two times with water, evaporated to dryness and purified withCombiFlash to afford 0.36 g of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 1.27 (s, 9H), 2.84 (t, 2H), 3.46 (m, 2H), 6.17 (m, 1H), 6.35(m, 2H), 7.52 (m, 1H), 8.08 (m, 1H), 12.89 (m, 1H).

b)3-tert-butyl-N-(2-(5-(3-chloro-4-cyano-2-methylphenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide

4-amino-2-chloro-3-methylbenzonitrile (0.200 g, 1.20 mmol) was added toa solution of water (2 ml) and conc. HCl (2 ml) and the mixture wasstirred vigorously, heated to 80° C. for 15 min and then cooled to −10°C. Sodium nitrite (0.091 g, 1.32 mmol) was dissolved in 0.5 ml of waterand added drop wise to the cooled reaction mixture. After 40 min, themixture was filtered and3-tert-butyl-N-(2-(furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide (0.345 g,1.32 mmol) dissolved in acetone (3 ml) was added to the filtrate. Then,a solution of iron (II) chloride tetra hydrate in water (3 ml) was addedportion wise and the mixture was stirred for 15 h at RT. Water (25 ml)was added to the reaction mixture and extracted three times with EtOAc.The combined organic layers were washed with saturated aqueous NaHCO₃and water and dried with Na₂SO₄, filtered and evaporated to dryness.CombiFlash purification afforded 0.013 g of the title compound. ¹H-NMR(400 MHz; d6-DMSO): δ 1.34 (s, 9H), 3.03 (t, 2H), 3.77 (m, 2H), 6.28 (d,1H), 6.62 (m, 2H), 7.12 (m, 1H), 7.50 (d, 1H), 7.65 (d, 1H).

Example 75(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methoxythiazole-2-carboxamidea) Ethyl 5-methoxythiazole-2-carboxylate

A mixture of ethyl 2-(2-methoxy-2-oxoethylamino)-2-oxoacetate (1.00 g,5.29 mmol) and phosphorus pentasulfide (1.29 g, 5.82 mmol) in chloroform(20 ml) was stirred at 60° C. for 7 h. To the cooled reaction mixtureDCM (100 ml) was added and the mixture was washed with water (50 ml) andbrine (50 ml). Organic phase was dried over Na₂SO₄ and evaporated.Evaporation residual was dissolved in dry MeCN (10 ml) and phosphoruspentoxide (0.75 g, 5.29 mml) was added and the mixture was heated toreflux for 4.5 h. To the cooled reaction mixture water (35 ml) was addedand the mixture was extracted with EtOAc (3×50 ml). Combined organicfractions were dried over Na₂SO₄ and evaporated to give crude product,which was purified twice by CombiFlash (1^(st) column: silica, eluent:0-100% EtOAc in heptane; 2^(nd) column: C-18, eluent: 0-100% MeCN inwater) to yield 73 mg (7%) of the title compound. ¹H-NMR (400 MHz;CDCl₃): δ 1.42 (t, 3H), 4.01 (s, 3H), 4.43 (q, 2H), 7.30 (s, 1H).

b) 5-methoxythiazole-2-carboxylic Acid

To a solution of ethyl 5-methoxythiazole-2-carboxylate (73 mg, 0.39mmol) in THF (1 ml) 1 M LiOH-solution (0.78 ml, 0.78 mmol) was added.Reaction mixture was stirred at RT for 1 h. Reaction was quenched byadding 1 M HCl solution until pH was about 5. Solvents were evaporatedand thus obtained crude title compound was used without purification.¹H-NMR (400 MHz; d6-DMSO): δ 3.88 (s, 3H), 7.12 (s, 1H).

c)(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methoxythiazole-2-carboxamide

(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (86 mg,0.33 mmol) was coupled with 5-methoxythiazole-2-carboxylic acid (90 mg,0.40 mmol) using the method of Example 34(d). Crude product was purifiedby CombiFlash (column: silica, eluent: 0-10% MeOH in DCM) to yield 12 mg(9%) of the title compound. ¹H-NMR (400 MHz; CDCl₃): δ 1.23 (d, 3H),3.99 (s, 3H), 4.26 (dd, 1H), 4.40-4.46 (m, 1H), 4.49-4.59 (m, 1H), 6.63(d, 1H), 7.22 (s, 1H), 7.49 (d, 1H), 7.68 (d, 1H), 7.78 (dd, 1H), 8.10(broad d, 1H) overlapping with 8.13 (d, 1H).

Example 76N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamide

The title compound was prepared from4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.361 g,1.463 mmol), 5-Pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.305 g,1.610 mmol), DIPEA (0.382 ml, 2.195 mmol), HOBt (0.297 g, 2.195 mmol)and EDCI (0.421 g, 2.195 mmol) using the method of Example 75(b)affording 0.022 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ3.71 (m, 2H), 4.38 (t, 2H), 6.97 (m, 1H), 7.23 (m, 1H), 7.48 (m, 1H),7.86 (m, 2H), 7.97 (m, 1H), 8.09 (m, 1H), 8.17 (m, 1H), 8.40-8.71 (m,2H), 8.98 (m, 1H), 13.82 (m, 1H).

Example 77(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamidea) 5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylic Acid

Ethyl 5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylate (0.436 g, 2.189mmol) was dissolved in methanol (20 ml). A solution of cesium carbonate(1.426 g, 4.38 mmol) in 20 ml of water was added and the reactionmixture was stirred at RT for 18 h. Solvents were evaporated and theresidue was taken into a mixture of ethyl acetate and water, pH wasadjusted to 2.5 with 10% citric acid solution and the layers wereseparated. Water layer was extracted three times with ethyl acetate andthe combined organic layers were dried with Na₂SO₄, filtered andevaporated affording 0.246 g of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 1.49 (s, 6H), 5.75 (m, 1H), 6.60 (s, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide

5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylic acid (0.088 g, 0.515mmol) and DIPEA (0.090 ml, 0.515 mmol) were dissolved in 5 ml of dryDCM. Anhydrous HOBt (0.070 g, 0.515 mmol), and EDCI (0.099 g, 0.515mmol) were added. After stirring at RT for 30 min the(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.112 g,0.430 mmol) dissolved in 1 ml of dry DMF was added to the reactionmixture. After overnight stirring at RT a mixture of5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylic acid (0.088 g, 0.515mmol), DIPEA (0.090 ml, 0.515 mmol), anhydrous HOBt (0.070 g, 0.515mmol) and EDCI (0.099 g, 0.515 mmol) dissolved in 5 ml of dry DCM wasadded to the reaction mixture. After 3 h the solvents were evaporatedand the residue was purified by CombiFlash using MeOH in DCM as aneluent. Product fractions were combined and evaporated to give 58 mg ofthe product. ¹H-NMR (400 MHz; CDCl₃): δ 1.23 (d, 3H), 1.65 (s, 6H), 4.26(m, 1H), 4.43 (m, 1H), 4.58 (m, 1H), 6.60 (s, 1H), 6.63 (d, 1H), 7.49(d, 1H), 7.68 (d, 1H), 7.83 (d, 1H), 7.90 (d, 1H), 8.07 (d, 1H).

Example 78(S)-5-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamidea)2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile

The title compound was prepared from 4-bromo-2,6-difluorobenzonitrile(2.5 g, 11.47 mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.51 g, 12.61 mmol) using the method of Example 34(a) producing 3.61 gof title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.52-1.67 (m, 3H),1.81-1.87 (m, 1H), 1.95-1.99 (m, 1H), 2.33-2.41 (m, 1H), 3.59-3.65 (m,1H), 3.94-3.98 (m, 1H), 5.36-5.39 (m, 1H), 6.77 (d, 1H), 7.62 (s, 1H),7.64 (s, 1H), 7.66 (d, 1H).

b) 2,6-difluoro-4-(1H-pyrazol-5-yl)benzonitrile

The title compound was prepared from2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile(3.32 g, 11.48 mmol) using the method of Example 34(b) affording 2.38 gof the product. ¹H-NMR (400 MHz; d6-DMSO): δ 7.04 (m, 1H), 7.83 (s, 1H),7.86 (s, 1H), 7.91 (m, 1H), 13.37 (s, 1H).

c) (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile

The title compound was prepared from2,6-difluoro-4-(1H-pyrazol-5-yl)-benzonitrile (1.39 g, 6.78 mmol) and(S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.423 g, 8.12 mmol),triphenylphosphine (2.129 g, 8.12 mmol) and DIAD (1.578 ml, 8.12 mmol)using the method of Example 34(c) affording 0.70 g of the titlecompound. ¹H-NMR (400 MHz; d6-DMSO): δ 0.95 (d, 3H), 3.22 (m, 1H), 4.01(m, 2H), 7.02 (d, 1H), 7.78 (m, 1H), 7.81 (m, 1H), 7.88 (d, 1H).

d)(S)-5-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.7g, 2.67 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.494 g, 3.20mmol), HOBt (0.433 g, 3.20 mmol), DIPEA (0.558 ml, 3.20 mmol) and EDCI(0.614 g, 3.20 mmol) using the method of Example 34(d) producing 0.29 gof the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.17 (m, 3H), 4.32(m, 2H), 4.44 (m, 1H), 6.97 (m, 1H), 7.31 (m, 1H), 7.71 (m, 2H), 7.83(m, 1H), 8.44 (m, 1H), 14.15 (m, 1H).

Example 79 N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamidea) 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile

The title compound was prepared from2,6-difluoro-4-(1H-pyrazol-5-yl)-benzonitrile (1.50 g, 7.31 mmol) andtert-butyl N-(2-hydroxyethyl)carbamate (0.96 ml, 6.09 mmol),triphenylphosphine (1.918 g, 7.31 mmol) and DIAD (1.200 ml, 6.09 mmol)using the method of Example 34 (c) affording 0.30 g of the titlecompound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.60 (m, 2H), 2.94 (t, 2H), 4.14(t, 2H), 7.01 (d, 1H), 7.79 (m, 2H), 7.88 (d, 1H).

b)N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamide

The title compound was prepared from4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.3 g,0.773 mmol), 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.161 g,0.851 mmol), DIPEA (0.202 ml, 1.160 mmol), HOBt (0.157 g, 1.160 mmol)and EDCI (0.222 g, 1.160 mmol) using the method of Example 34(d)affording 0.06 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ3.70 (t, 2H), 4.39 (t, 2H), 7.01 (d, 1H), 7.79 (m, 2H), 7.88 (d, 1H).

Example 805-(1H-imidazol-4-yl)-1-methyl-N-(2-(3-(4-nitro-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-3-carboxamidea)5-(4-Nitro-3-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

The title compound was prepared from 5-bromo-2-nitrobenzotrifluoride (5g, 18.52 mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(5.67 g, 20.37 mmol) using the method of Example 34(a). Reactionafforded 3.90 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ1.49-1.68 (m, 3H), 1.82 (m, 1H), 1.94 (m, 1H), 2.38 (m, 1H), 3.61 (m,1H), 3.99 (d, 1H), 5.31 (m, 1H), 6.78 (d, 1H), 7.66 (d, 1H), 8.10 (m,1H), 8.19 (m, 1H), 8.32 (d, 1H).

b) 5-(4-nitro-3-(trifluoromethyl)phenyl)-1H-pyrazole

The title compound was prepared from5-(4-Nitro-3-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(2.693 g, 7.89 mmol) using the method of Example 34(b) affording 1.69 gof the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 7.08 (m, 1H), 7.92(m, 1H), 8.22 (d, 1H), 8.35 (m, 1H), 8.38 (m, 1H), 13.45 (m, 1H).

c) 2-(3-(4-nitro-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)ethanamine

The title compound was prepared from5-(4-nitro-3-(trifluoromethyl)phenyl)-1H-pyrazole (1.69 g, 6.57 mmol)and tert-butyl 2-hydroxyethylcarbamate (1.059 g, 6.57 mmol) using themethod of Example 34(c) to afford 1.24 g of the title compound. ¹H-NMR(400 MHz; d6-DMSO): δ 3.33 (m, 2H), 4.53 (t, 2H), 7.13 (d, 1H), 8.00 (d,1H), 8.38 (m, 1H), 13.45 (m, 1H).

d)5-(1H-imidazol-4-yl)-1-methyl-N-(2-(3-(4-nitro-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-3-carboxamide

The title compound was prepared from2-(3-(4-nitro-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)ethanamine(0.062 g, 0.208 mmol) and5-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.05 g,0.260 mmol) HOBt (0.035 g, 0.260 mmol), DIPEA (0.091 ml, 0.520 mmol) andEDCI (0.050 g, 0.260 mmol) using the method of Example 34(d) to afford0.128 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 3.71 (m,3H), 4.40 (t, 2H), 7.04 (s, 1H), 7.05 (d, 1H), 7.88 (d, 1H), 8.03 (s,1H), 8.22 (m, 1H), 8.31-8.33 (m, 2H), 8.40 (t, 1H), 9.03 (m, 1H).

Example 81N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-3-(1-(hydroxyimino)-ethyl)-1H-pyrazole-5-carboxamidea) 2-Nitro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile

The title compound was prepared from 4-chloro-2-nitrobenzonitrile (3.00g, 16.43 mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(5.48 g, 19.72 mmol) using the method of Example 34(a) affording 1.26 gof the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.56-1.62 (m, 3H),1.81-1.85 (m, 1H), 1.95-1.99 (m, 1H), 2.33-2.47 (m, 1H), 3.68-3.75 (m,1H), 4.01-4.04 (m, 1H), 5.31-5.34 (m, 1H), 6.84 (d, 1H), 7.69 (d, 1H),8.13 (m, 1H), 8.32 (d, 1H), 8.60 (d, 1H).

b) 2-Nitro-4-(1H-pyrazol-5-yl)benzonitrile

The title compound was prepared from2-Nitro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile(1.26 g, 4.22 mmol) using the method of Example 34(b) affording 0.828 gof the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 7.09 (m, 1H), 7.94(m, 1H), 8.20 (d, 1H), 8.37 (d, 1H), 8.73 (s, 1H), 13.39 (s, 1H).

c) 4-(1-(2-Aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile

The title compound was prepared from2-nitro-4-(1H-pyrazol-5-yl)benzonitrile (0.828 g, 3.87 mmol) andtert-butyl 2-hydroxyethylcarbamate (0.748 g, 4.64 mmol) using the methodof Example 34(c) affording 0.633 g of the title compound. ¹H-NMR (400MHz; d6-DMSO): δ 3.21-3.29 (m, 2H), 4.02-4.04 (m, 2H), 7.02 (d, 1H),7.88 (d, 1H), 8.13 (d, 1H), 8.29 (m, 1H), 8.50 (d, 1H).

d)5-Acetyl-N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-3-carboxamide

The title compound was prepared from4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (0.50 g, 1.94mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.30 g, 1.94 mmol), HOBt(0.31 g, 2.33 mmol), DIPEA (0.41 ml, 2.33 mmol) and EDCI (0.44 g, 2.33mmol) using the method of Example 34(d) producing 0.56 g of the titlecompound. ¹H-NMR (400 MHz; d6-DMSO): δ 2.48 (s, 3H), 3.69-3.73 (m, 2H),4.39 (t, 2H), 7.05 (d, 1H), 7.30 (s, 1H), 7.88 (d, 1H), 8.18 (d, 1H),8.32 (d, 1H), 8.66 (d, 1H), 14.16 (s, 1H).

e)N-(2-(3-(4-Cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-3-(1-(hydroxy-imino)ethyl)-1H-pyrazole-5-carboxamide

5-Acetyl-N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-3-carboxamide(0.17 g, 0.43 mmol) was dissolved in ethanol (15 ml). Sodium acetate(0.071 g, 0.86 mmol) and hydroxylamine hydrochloride (0.060 g, 0.86mmol) was added and the reaction mixture was stirred at RT for 1.5 h.After addition of pyridine (5 ml) stirring was continued for 65 h. Thereaction mixture was evaporated to dryness, co-evaporated two times withtoluene and dissolved the residue in ethyl acetate. It was then washedtwo times with water, dried with Na₂SO₄ and purified with CombiFlashusing DCM and methanol as eluents affording 0.034 g of the titlecompound. ¹H-NMR (400 MHz; d6-DMSO): δ 2.11-2.15 (m, 3H), 3.68-3.71 (m,2H), 4.39 (t, 2H), 7.05-7.06 (m, 1H), 7.88 (d, 1H), 8.17-8.20 (m, 1H),8.32-8-35 (m, 1H), 8.68 (d, 1H).

Example 82(R)—N-(1-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamidea)4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-(trifluoromethyl)-benzonitrile

The title compound was prepared from 4-iodo-2-(trifluoromethyl)benzonitrile (5.97 g, 22.6 mmol) using the method of Example 34(a)affording 5.34 g of the title compound after column purification.

b) 4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)benzonitrile

The title compound was prepared from4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-(trifluoromethyl)benzonitrileusing the method of Example 34(b) affording 3.94 g of the titlecompound. ¹H-NMR (400 MHz; d6-DMSO): δ 7.07 (m, 1H), 7.91 (m, 1H), 8.19(d, 1H), 8.31 (d, 1H), 8.35 (s, 1H), 13.33 (s, 1H).

c) (R)-2-(1-bromopropan-2-yl)isoindoline-1,3-dione

(R)-2-(1-hydroxypropan-2-yl)isoindoline-1,3-dione (1.3 g, 50.0 mmol) washeated to reflux with phosphorustribromide (9.2 ml, 34 mmol) for 30 min.The reaction mixture was cooled to RT and ice was added to the reactionmixture. After stirring the mixture was filtered and the precipitate waswashed with cold water and dried in vacuum to afford 12.37 g of thetitle compound.

d)(R)-4-(1-(2-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile

4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)benzonitrile (1.0 g, 4.22 mmol)and (R)-2-(1-bromopropan-2-yl)isoindoline-1,3-dione (1.35 g, 5.06 mmol)were weighed into a microreaction vial and DMF (10 ml) was added. Then,potassium carbonate (1.165 g, 8.43 mmol), copper(I) iodide (0.040 g,0.21 mmol) and N, N′-dimethyl-ethylenediamine (0.004 ml, 0.042 mmol)were added and the reaction vial was capped under nitrogen and washeated in the microwave oven (Biotage) at 160° C. for 30 min. Themixture was then poured into water and extracted with DCM and 2%MeOH/DCM. Organic layers were combined, dried with Na₂SO₄, filtered andevaporated to dryness. CombiFlash purifications using normal andreversed phase columns afforded 0.199 g of the title compound. ¹H-NMR(400 MHz; d6-DMSO): δ 1.54 (m, 3H), 4.55-4.65 (m, 3H), 6.95 (d, 1H),7.77 (m, 4H), 7.82 (m, 1H), 7.86-7.89 (m, 2H), 8.01 (d, 1H).

e)(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile

(R)-4-(1-(2-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-3-yl)-2-(trifluoro-methyl)benzonitrile(0.199 g, 0.469 mmol) was mixed with ethanol (15 ml). Hydrazine hydrate(0.227 ml, 4.69 mmol) was added and the mixture was refluxed for 3 h.After cooling to RT the precipitate was filtered and washed withethanol. The filtrate was purified with CombiFlash using DCM andmethanol as eluents. Drying in the vacuum afforded 0.080 g of the titleproduct. ¹H-NMR (400 MHz; d6-DMSO): δ 0.96 (d, 3H), 3.21-3.29 (m, 2H),4.01-4.03 (m, 2H), 7.05 (d, 1H), 7.88 (d, 2H), 8.18 (d, 1H), 8.26-8.28(m, 1H), 8.31 (s, 1H).

f)(R)—N-(1-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide

(The title compound was prepared from(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile(0.080 g, 0.272 mg) and 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid(0.053 g, 0.299 mmol) using the method of Example 34(d) affording 0.092g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H),4.30-4.39 (m, 2H), 4.42-4.51 (m, 1H), 6.61 (m, 1H), 7.03 (d, 1H), 7.76(m, 1H), 7.86 (d, 1H), 8.17 (d, 1H), 8.27 (m, 2H), 8.34-8.36 (m, 1H),13.69 (m, 1H).

Example 83(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)-1H-pyrazole-5-carboxamidea)2-chloro-3-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-benzonitrile

The title compound was prepared from2-chloro-4-iodo-3-methylbenzonitrile (3.52 g, 12.68 mmol) and1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.88 g, 13.95 mmol) using the method of Example 34(a) affording 2.62 gof the title compound.

b) 2-chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile

The title compound was prepared from2-chloro-3-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile(2.62 g, 8.68 mmol) using the method of Example 34(b) affording 1.66 gof the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 6.66 (t, 1H), 7.69(d, 1H), 7.84 (d, 1H), 7.90 (m, 1H), 13.25 (m, 1H).

c) (S)-2-(tert-butoxycarbonylamino)propyl methanesulfonate

(S)-tert-Butyl 1-hydroxypropan-2-ylcarbamate (10.25 g, 58.5 mmol) wasdissolved DCM (20 ml). Triethylamine (12.23 ml, 87.7 mmol) was added andthe solution was cooled to 0° C. under nitrogen. Methanesulfonylchloride(5.0 ml, 64.3 mmol) was diluted with DCM (5 ml) and added drop wise tothe reaction mixture keeping the temperature under 10° C. Afteraddition, the reaction mixture was allowed to warm up to RT and stirringwas continued for 36 h. Next, the reaction mixture was diluted with DCM(150 ml) and washed several times with NaHCO₃-solution and water, theorganic layer dried with Na₂SO₄, filtered and evaporated affording 8.78g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.06 (d, 3H), 1.38(s, 9H), 3.16 (s, 3H), 3.75 (m, 1H), 4.04 (m, 2H), 6.93 (m, 1H).

d) (S)-tert-butyl1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamate

2-Chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile (1.96 g, 8.96 mmol)was dissolved in toluene (20 ml). To this solution an aqueous solutionof NaOH (1M, 20 ml) and tetrabutylammonium bromide (0.58 g, 1.79 mmol)was added, respectively. (S)-2-(tert-butoxycarbonylamino)propylmethanesulfonate (4.54 g, 17.92 mmol) was dissolved in toluene (20 ml)and added to the reaction mixture. After 96 h of vigorous stirring at RTthe reaction mixture was diluted with toluene and washed several timeswith water, dried with Na₂SO₄, filtered and evaporated. After CombiFlashpurification using heptane/EtOAc as eluents, 1.85 g of the product wascollected. ¹H-NMR (400 MHz; d6-DMSO): δ 1.02 (d, 3H), 1.31 (s, 9H), 2.57(s, 3H), 3.91 (m, 1H), 4.13 (m, 2H), 6.62 (m, 1H), 6.87 (d, 1H), 7.66(d, 1H), 7.79 (d, 1H), 7.84 (d, 1H).

e)(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile

(S)-tert-butyl1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamate (1.85 g, 4.96 mmol) was dissolved in a mixture ofDCM:TFA:water (8:1.5:0.5, v:v:v, 20 ml) and stirred at RT for 22 h. Thereaction mixture was then diluted with DCM to 50 ml and washed withNaHCO₃, brine and water, and the organic layer was dried with Na₂SO₄,filtered and evaporated to dryness affording 1.19 g of the titlecompound. ¹H-NMR (400 MHz; d6-DMSO): δ 0.96 (d, 3H), 2.57 (s, 3H), 3.23(m, 1H), 4.02 (d, 2H), 6.64 (d, 1H), 7.67 (d, 1H), 7.83 (d, 1H), 7.87(d, 1H).

f)(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.2 g, 0.728 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.112 g,0.728 mmol), HOBt (0.128 g, 0.946 mmol), DIPEA (0.165 ml, 0.946 mmol)and EDCI (0.181 g, 0.946 mmol) using the method of Example 34(d)affording 0.117 g of the title compound. ¹H-NMR (400 MHz; CDCl₃): δ 1.27(d, 3H), 2.54 (s, 3H), 2.55 (s, 3H), 4.31 (m, 1H), 4.44 (m, 1H), 4.62(m, 1H), 6.44 (d, 1H), 7.51 (d, 1H), 7.54 (s, 2H), 11.14 (m, 1H).

Example 84N—((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)-1H-pyrazole-5-carboxamide(0.04 g, 0.097 mmol) as prepared in the previous Example was added inethanol (5 ml). Solid sodium borohydride (0.018 g, 0.487 mmol) was addedto the mixture and it was refluxed for 15 min under nitrogen. To thecooled solution a portion of 10 ml of saturated ammonium chloride wasadded and the mixture was extracted several times with DCM. The organicextracts were combined and washed with water, dried with Na₂SO₄,filtered and evaporated to dryness affording 0.040 g of the titlecompound. ¹H-NMR (400 MHz; CDCl₃): δ 1.25 (m, 3H), 1.51 (m, 3H), 2.49(d, 3H), 3.72 (m, 1H), 4.29 (m, 1H), 4.41 (m, 1H), 4.61 (m, 1H), 4.99(m, 1H), 6.42 (d, 1H), 6.56 (s, 1H), 7.43-7.50 (m, 3H), 7.53 (d, 1H).

Example 85(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methylisoxazole-3-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.2 g, 0.728 mmol), 5-methylisoxazole-3-carboxylic acid (0.120 g, 0.946mmol), HOBt (0.128 g, 0.946 mmol), DIPEA (0.165 ml, 0.946 mmol) and EDCI(0.181 g, 0.946 mmol) using DCM as solvent using the method of Example34(d) affording 0.114 g of the title compound. ¹H-NMR (400 MHz; CDCl₃):δ 1.26 (m, 3H), 2.48 (d, 3H), 2.56 (m, 3H), 4.29 (m, 1H), 4.43 (m, 1H),4.59 (m, 1H), 6.41 (m, 1H), 6.44 (d, 1H), 7.44 (m, 1H), 7.50 (d, 1H),7.56 (d, 1H), 7.62 (d, 1H).

Example 86(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.2 g, 0.728 mmol), 1,3-thiazole-4-carboxylic acid (0.113 g, 0.874mmol), HOBt (0.118 g, 0.874 mmol), DIPEA (0.152 ml, 0.874 mmol) and EDCI(0.167 g, 0.874 mmol) using DCM as solvent using the method of Example34(d) affording 0.88 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO):δ 1.16 (d, 3H), 2.51 (s, 3H), 4.37 (m, 2H), 6.61 (d, 1H), 7.67 (d, 1H),7.83-7.85 (m, 2H), 8.27 (d, 1H), 8.56 (d, 1H), 9.20 (d, 1H).

Example 87(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.15 g, 0.546 mmol), 5-trifluoromethyl-1H-pyrazole-3-carboxylic acid(0.108 g, 0.601 mmol), HOBt (0.111 g, 0.819 mmol), DIPEA (0.143 ml,0.819 mmol) and EDCI (0.157 g, 0.819 mmol) using DCM as solvent usingthe method of Example 34(d) affording 0.098 g of the title compound.¹H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 2.48 (s, 3H), 4.30 (m, 2H),4.46 (m, 1H), 6.60 (d, 1H), 7.21 (m, 1H), 7.60 (d, 1H), 7.79 (d, 1H),7.85 (d, 1H), 8.51 (m, 1H), 14.39 (m, 1H).

Example 88(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.059 g, 0.331 mmol), 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid(0.091 g, 0.331 mmol), HOBt (0.068 g, 0.497 mmol), DIPEA (0.087 ml,0.497 mmol) and EDCI (0.096 g, 0.497 mmol) using DCM as solvent usingthe method of Example 34(d) affording 0.065 g of the title compound.¹H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.53 (s, 3H), 4.28-4.38 (m,2H), 4.43-4.51 (m, 1H), 6.60 (d, 2H), 6.81-6.91 (m, 2H), 7.66 (d, 1H),7.77 (s, 1H), 7.82 (d, 1H), 7.85 (m, 1H), 8.31 (m, 1H), 13.69 (m, 1H).

Example 89(R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamidea) (R)-2-(tert-butoxycarbonylamino)propyl methanesulfonate

The title compound was prepared from (R)-tert-butyl1-hydroxypropan-2-ylcarbamate (9.45 g, 53.9 mmol) using the method ofExample 83(c) affording 11.48 g of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 1.06 (d, 3H), 1.38 (s, 9H), 3.16 (s, 3H), 3.74 (m, 1H), 4.04(d, 2H), 6.94 (m, 1H).

b) (R)-tert-Butyl1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamate

2-chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile (0.5 g, 2.297 mmol)was dissolved in dry acetonitrile (5 ml) under nitrogen and cooled to 0°C. Sodium ethoxide (0.313 g, 4.59 mmol) was added and the reactionmixture was stirred for 25 min and allowed to warm up to RT.(R)-2-(tert-butoxycarbonylamino)propyl methanesulfonate (0.582 g, 2.297mmol) was dissolved in 5 ml of dry acetonitrile and added dropwise tothe reaction mixture. The reaction mixture was refluxed for 15 h andthen the solvents were evaporated. The residue was taken into EtOAc,washed several times with saturated aqueous NaHCO₃ and water, dried withNa₂SO₄ and evaporated to dryness. CombiFlash purification afforded 0.437g of the title compound using heptane/EtOAc-system as an eluent. ¹H-NMR(400 MHz; d6-DMSO): δ 1.02 (d, 3H), 1.31 (s, 9H), 2.57 (s, 3H), 3.91 (m,1H), 4.13 (m, 2H), 6.62 (m, 1H), 6.87 (d, 1H), 7.66 (d, 1H), 7.78 (d,1H), 7.83 (d, 1H).

c)(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile

The title compound was prepared from (R)-tert-butyl1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamate(0.437 g, 1.166 mmol) using the method of Example 83(e) affording 0.306g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 0.96 (d, 3H), 2.57(s, 3H), 3.18-3.26 (m, 1H), 4.01 (d, 2H), 6.64 (d, 1H), 7.67 (d, 1H),7.83 (d, 1H), 7.86 (d, 1H).

d)(R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamide

The title compound was prepared from(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.3 g, 1.092 mmol), 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.227g, 1.201 mmol), DIPEA (0.285 ml, 1.638 mmol), HOBt (0.221 g, 1.638 mmol)and EDCI (0.314 g, 1.638 mmol) using the method of Example 34(d)affording 0.214 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ1.15-1.21 (m, 3H), 2.54 (s, 3H), 4.28-4.41 (m, 2H), 4.45-4.54 (m, 2H),6.61 (d, 1H), 7.22 (d, 1H), 7.45-7.52 (m, 1H), 7.62-7.70 (m, 1H),7.76-1.86 (m, 2H), 8.09-8.18 (m, 1H), 8.25-8.47 (m, 1H), 8.53-8.57 (m,1H), 8.99 (d, 1H).

Example 90(R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared from(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.077 g, 0.280 mmol), 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid(0.055 g, 0.308 mmol), DIPEA (0.073 ml, 0.420 mmol), HOBt (0.057 g,0.420 mmol) and EDCI (0.081 g, 0.420 mmol) using the method of Example34(d) affording 0.090 g of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 1.15-1.17 (m, 3H), 2.52 (s, 3H), 4.32-4.35 (m, 2H),4.44-4.51 (m, 1H), 6.61 (d, 2H), 7.65-7.67 (m, 1H), 7.75-7.79 (m, 1H),7.82 (d, 1H), 7.84 (d, 1H), 8.30 (m, 2H), 8.35 (m, 2H), 13.69 (m, 1H).

Example 91(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-ethyl-1,2,4-oxadiazole-5-carboxamide

(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.77 mmol) was coupled with 3-ethyl-1,2,4-oxadiazole-5-carboxylic acid(131 mg, 0.92 mmol) using the method of Example 34(d). Crude product wassuspended in MeCN and the precipitation was filtered to yield 34 mg(11%) of the title compound. Filtrate was purified by CombiFlash(column: C-18, eluent: 0-100% MeCN) to yield additional 118 mg (40%) oftitle product. Combined total yield was 152 mg (51%). ¹H-NMR (400 MHz;d6-DMSO): δ 1.18 (d, 3H), 1.26 (t, 3H), 2.81 (q, 2H), 4.31-4.37 (m, 2H),4.40-4.52 (m, 1H), 6.95 (d, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 7.97 (d,1H), 8.06 (d, 1H), 9.39 (broad d, 1H).

Example 92(E)-4-(5-(((3-tert-butyl-1H-pyrazole-5-carbonyl)diazenyl)methyl)-furan-2-yl)-2-(trifluoromethyl)benzonitrilea) 4-bromo-2-(trifluoromethyl)-benzonitrile

To the cooled and vigorously stirred suspension of4-amino-2-(trifluoro-methyl)benzonitrile (5.00 g, 26.8 mmol) in 25 ml ofconcentrated hydrogen bromide a solution of sodium nitrite (1.85 g, 26.8mmol) in 10 ml of water was added dropwise while keeping the temperaturebelow 5° C. during the addition. This mixture was then poured into asolution of copper(I)bromide (3.85 g, 26.8 mmol) in 30 ml ofconcentrated hydrogen bromide and stirred at RT for two hours. Thereaction mixture was then poured into an ice-water (300 ml) mixture andextracted four times with ethyl acetate. The combined extracts werewashed with saturated sodium bicarbonate and water, dried and evaporatedto dryness. Combiflash purification using heptane/ethyl acetate aseluent system afforded 5.1 g of the title product. ¹H-NMR (400 MHz;d6-DMSO): δ 8.13 (d, 1H), 8.18 (d, 1H), 8.27 (s, 1H)

b) 4-(5-formylfuran-2-yl)-2-(trifluoromethyl)benzonitrile

To the stirred solution of 5-formylfuran-3-boronic acid (0.31 g, 2.2mmol), palladium (10%) in carbon (0.090 g) and sodium carbonate (0.85 g,8.0 mmol) in ethanol (10 ml) was added a solution of4-bromo-2-(trifluoromethyl)benzonitrile (0.50 g, 0.19 mmol) in ethanol(10 ml) under nitrogen atmosphere. The reaction mixture was refluxed fortwo hours, and then cooled to RT and diluted with ethanol. The mixturewas filtered through a pad of Celite, washed with ethanol and thefiltrate was evaporated to dryness. Combiflash purification usingheptane/ethyl acetate as eluent system afforded 0.20 g of the titlecompound. ¹H-NMR (400 MHz; d6-DMSO): δ 7.73 (d, 1H), 7.76 (d, 1H), 8.31(m, 1H), 8.33 (m, 1H), 8.39 (m, 1H), 9.71 (s, 1H).

c)(E)-4-(5-(((3-tert-butyl-1H-pyrazole-5-carbonyl)diazenyl)methyl)furan-2-yl)-2-(trifluoromethyl)benzonitrile

To the solution of 3-tert-butyl-1H-pyrazole-5-carbohydrazide (0.076 g,0.41 mmol) in 10 ml of ethanol4-(5-formylfuran-2-yl)-2-(trifluoromethyl)benzonitrile (0.10 g, 0.37mmol) was added and the mixture was stirred at RT for 36 h. The solventwas evaporated and the residue purified with Combiflash usingDCM/methanol as eluent system affording fractions containing the titlecompound. After treatment of these fractions with DCM the productprecipitated out producing 0.048 g of title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 1.31 (s, 9H), 6.55 (m, 1H), 7.12 (d, 1H), 7.65 (d, 1H), 8.24(m, 2H), 8.28 (m, 1H), 8.48 (m, 1H), 11.82 (m, 1H), 13.07 (m, 1H).

Example 93 Pyridine-2-carboxylicacid{1-[5-(3,4-dichlorophenyl)furan-2-yl]-meth-(E)-ylidene}hydrazide andPyridine-2-carboxylicAcid{1-[5-(3,4-dichlorophenyl)furan-2-yl]meth-(Z)-ylidene}hydrazide

A stirred solution of 2-picolinyl hydrazide (0.29 g, 2.11 mmol) and5-(3,4-dichlorophenyl)furfural (0.45 g, 1.87 mmol) in ethanol (24 ml)was refluxed for 2.5 h under nitrogen atmosphere. Then the solution wascooled and stirring was continued at 0° C. A precipitated solid wasfiltered and washed with icecold ethanol to afford the mixture ofpyridine-2-carboxylic acid{1-[5-(3,4-dichlorophenyl)furan-2-yl]meth-(Z)-ylidene}hydrazide andpyridine-2-carboxylic acid{1-[5-(3,4-dichlorophenyl)-furan-2-yl]meth-(E)-ylidene}hydrazide (Z:E33:67). The isomers were purified and separated by flash chromatographyon silica gel using first heptane/EtOAc (33:67-0:100) as a gradienteluent to afford the Z isomer and then CH₂Cl₂/MeOH (99.5:0.5) as aneluent to afford the E isomer.

Pyridine-2-carboxylicacid-{1-[5-(3,4-Dichlorophenyl)furan-2-yl]meth-(Z)-ylidene}-hydrazide:¹H NMR (400 MHz, DMSO-d₆): 7.24 (1H, d), 7.49 (1H, d), 7.61 (1H, s),7.75-7.80 (1H, m), 7.96 (1H, d), 8.12-8.24 (3H, m), 8.27 (1H, d), 8.87(1H, m), 12.71 (1H, s).

Pyridine-2-carboxylicacid-{1-[5-(3,4-Dichlorophenyl)furan-2-yl]meth-(E)-ylidene}-hydrazide:¹H NMR (400 MHz, DMSO-d₆): 7.08 (1H, d), 7.33 (1H, d), 7.67-7.70 (1H,m), 7.74 (1H, distorted d), 7.79 (1H, distorted dd), 8.04 (1H, d), 8.07(1H, td), 8.14 (1H, distorted d), 8.59 (1H, s), 8.73 (1H, d), 12.29 (1H,s).

Example 94(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-methylthiazol-4-yl)-1H-pyrazole-3-carboxamidea) Methyl 3-(2-methylthiazol-4-yl)-1H-pyrazole-5-carboxylate

Methyl 3-acetyl-1H-pyrazole-5-carboxylate (100 mg, 0.595 mmol) wasrefluxed with bromine (143 mg, 0.892 mmol) in chloroform. Solvent wasevaporated and thus obtained methyl3-(2,2-dibromoacetyl)-1H-pyrazole-5-carboxylate (191 mg, 0.586 mmol) wastreated with thioacetamide (44 mg, 0.586 mmol) in refluxing methanol.Solvent was evaporated and the residue was dissolved in DCM and washedwith water. Organic phase was dried over Na₂SO₄, filtered and evaporatedto give 133 mg (102%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO):δ 2.71 (s, 3H), 3.83 (s, 3H), 7.10 (s, 1H), 7.90 (s, 1H) 14.0 (broad s,1H).

b) 3-(2-methylthiazol-4-yl)-1H-pyrazole-5-carboxylic Acid

A solution of methyl 3-(2-methylthiazol-4-yl)-1H-pyrazole-5-carboxylate(0.586 mmol) in 5 ml of THF and 1 ml of MeOH was treated with 2 ml of 1M NaOH-solution at RT over three nights. Solvent was evaporated and theresidue was taken up in water and washed with DCM. 1 M HCl was added tothe water phase until pH was 5. The water phase was washed twice withDCM and neutralized by 1 M sodiumbicarbonate solution. The water phasewas evaporated from toluene and the evaporation residual suspended toEtOH. Thus obtained solid was filtered to give 151 mg (123%) of thetitle compound. ¹H-NMR (400 MHz; d6-DMSO): δ 2.69 (s, 3H), 6.68 (s, 1H),7.60 (s, 1H), 12.89 (bs, 1H).

c)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-methylthiazol-4-yl)-1H-pyrazole-3-carboxamide

3-(2-Methylthiazol-4-yl)-1H-pyrazole-5-carboxylic acid (0.586 mmol) wascoupled with(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile using themethod of Example 34(d). Crude product was purified by CombiFlash(silica column, eluent: 50-100% EtOAc in heptane) to obtain 24 mg (18%)of the title compound ¹H-NMR (400 MHz; CDCl₃): δ 1.24 (d, 3H), 2.77 (s,3H), 4.28 (dd, 1H), 4.44 (dd, 1H), 4.55-4.67 (m, 1H), 6.59 (d, 1H), 7.06(s, 1H), 7.38 (s, 1H), 7.49 (d, 1H), 7.60 (d, 1H), 7.74 (dd, 1H), 7.82(d, 1H), 8.06 (d, 1H), 11.75 (bs, 1H).

Example 951-(5-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-pyrazol-3-yl)ethyl2-(dimethylamino)acetate

A solution ofN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamideof Example 56 (90 mg, 0.225 mmol) in 2 ml of DCM was added to asuspension of N,N-dimethylglycine (47 mg, 0.45 mmol), DIPEA (0.13 ml;0.75 mmol), anhydrous HOBt (61 mg, 0.45 mmol) and EDCI (87 mg, 0.45mmol) in 2 ml of DCM. The reaction mixture was stirred at RT over threenights. The mixture was diluted with DCM and washed with water. Organicphase was dried over Na₂SO₄, filtered and evaporated. Crude product waspurified twice by CombiFlash (1^(st) column: silica, eluent: 0-10% MeOHin DCM; 2^(nd) column: alumina, eluent: 0-10% MeOH in DCM) to obtain 26mg (36%) of the title compound. ¹H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H),1.66 (d, 3H), 2.35 (d, 6H), 3.20 (d, 2H), 4.25-4.33 (m, 1H), 4.37-4.45(m, 1H), 4.52-4.64 (m, 1H), 6.00 (q, 1H), 6.60 (m, 1H), 6.80 (s, 1H),7.50 (dd, 1H), 7.67 (m, 1H), 7.74-7.87 (m, 2H), 8.09 (d, 1H), 11.6 (bs,1H).

Example 96(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-6-(1H-pyrazol-1-yl)pyridazine-3-carboxamide

6-(1H-pyrazol-1-yl)pyridazine-3-carboxylic acid (100 mg, 0.53 mmol) wascoupled with(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile asdescribed in Example 34(d). Crude product was purified twice byCombiFlash (1^(st) column: silica, eluent: 0-100% EtOAc in heptane;2^(nd) column: silica, eluent: 0-15% MeOH in DCM) to obtain 54 mg (26%)of the title compound. ¹H-NMR (400 MHz; DMSO): δ 1.23 (d, 3H), 4.35-4.50(m, 2H), 4.51-4.64 (m, 1H), 6.75 (dd, 1H), 6.94 (d, 1H), 7.87 (d, 1H),7.92-7.98 (m, 2H), 8.03 (dd, 2H), 8.30 (m, 2H), 8.87 (d, 1H), 9.38 (d,1H).

Example 97(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-(dimethylamino)acetamido)thiazole-4-carboxamide

A solution of(S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamideof Example 57 (46 mg, 0.12 mmol) in 1 ml of DCM was added to asuspension of N,N-dimethylglycine (25 mg, 0.24 mmol), DIPEA (0.041 ml;0.24 mmol), anhydrous HOBt (32 mg, 0.24 mmol) and EDCI (46 mg, 0.24mmol) in 1 ml of DCM. The reaction mixture was stirred at RT over threenights. N,N-dimethylglycine (25 mg), DIPEA (0.021 ml), anhydrous HOBt(16 mg) and EDCI (23 mg) were added to the reaction mixture, andstirring was continued overnight. N,N-dimethylglycine (25 mg), DIPEA(0.082 ml) and EDCI (46 mg) were added twice the following two days.Three days after last addition of reagents the reaction was quenched byadding DCM and washing with water. Organic phase was dried over Na₂SO₄,filtered and evaporated. Crude product was purified twice by CombiFlash(1^(st) column: silica, eluent: 0-10% MeOH in DCM; 2^(nd) column:silica, eluent: 20-100% EtOAc in heptane) to obtain 3.2 mg (6%) of thetitle compound. ¹H-NMR (400 MHz; CDCl₃): δ 1.26 (d, 3H), 2.42 (s, 6H),3.25 (s, 2H), 4.32 (dd, 1H), 4.42 (dd, 1H), 4.53-4.63 (m, 1H), 6.62 (d,1H), 7.49 (d, 1H), 7.62 (d, 1H), 7.68 (d, 1H), 7.78 (s, 1H), 7.82 (dd,1H), 7.96 (d, 1H).

Example 98(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(cyanomethyl)thiazole-4-carboxamide

2-(Cyanomethyl)thiazole-4-carboxylic acid (280 mg, 0.10 mmol) wascoupled with(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile using themethod of Example 34(d). Crude product was purified twice by CombiFlash(1^(st) column: silica, eluent: 0-100% EtOAc in heptane; 2^(nd) column:C-18 silica, eluent: 0-100% MeCN in water) to obtain 4.9 mg (1%) of thetitle compound. ¹H-NMR (400 MHz; CDCl₃): δ 1.26 (d, 3H), 4.13 (s, 2H),4.31 (dd, 1H), 4.43 (dd, 1H), 4.55-4.67 (m, 1H), 6.63 (d, 1H), 7.49 (d,1H), 7.70 (d, 1H), 7.79 (dd, 1H), 7.84 (d, 1H), 7.97 (d, 1H), 8.12 (d,1H).

Example 99(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamidea) (S)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (1.06 g, 4.40 mmol),N-Boc-(S)-(−)-2-amino-1-butanol (1.0 g, 5.28 mmol) andtriphenylphosphine (1.73 g, 6.61 mmol) were dissolved in 15 ml of dryTHF under nitrogen atmosphere. DIAD (1.73 ml; 8.81 mmol) was addedslowly by syringe to cooled (0° C.) reaction mixture. After beingstirred overnight at RT, the reaction mixture was evaporated to dryness.The evaporation residue was dissolved in 20 ml of 10% HCl(g)/EtOH-solution and stirred at RT overnight to induceBoc-deprotection. Solvents were evaporated and the evaporation residuewas taken up in water and brine. Thus obtained solution was washed twicewith DCM, made alkaline (pH-12) by adding 2 M NaOH-solution, andextracted twice with DCM. The latter organic extracts were combined,dried over Na₂SO₄, filtered and evaporated to give 568 mg (47%) of thetitle compound. ¹H-NMR (400 MHz; d6-DMSO): δ. 0.87-0.94 (m, 3H),1.10-1.45 (m, 2H), 2.97-3.05 (m. 1H), 4.01 (dd, 1H), 4.13 (dd, 1H),4.68-4.86 (m, 1H), 6.97 (d, 1H), 7.86 (d, 1H), 7.95 (dd, 1H), 7.97 (dd,1H), 8.10-8.12 (m, 1H). MS [M+1]: m/z [274.8+1].

b)(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamide

(S)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg,0.73 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (123mg, 0.80 mmol) using the method of Example 34(d). Crude product waspurified twice by CombiFlash (1^(st) column: silica, eluent: 0-10% MeOHin DCM; 2^(nd) column: C-18 silica, eluent: 0-100% MeCN in water) toobtain 72 mg (24%) of the title compound. ¹H-NMR (400 MHz;d6-CDCl3/MeOD): δ 1.03 (t, 3H), 1.50-1.73 (m, 2H), 2.54 (s, 3H),4.30-4.46 (m, 3H), 6.63 (d, 1H), 7.42 (s, 2H), 7.57 (d, 1H), 7.73 (d,1H), 7.84 (d, 1H), 7.93 (s, 1H).

Example 100(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methylthiazole-2-carboxamide

5-Methyl-1,3-thiazole-2-carboxylic acid (55 mg, 0.38 mmol) was coupledwith (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100mg, 0.38 mmol) using the method of Example 34(d). Crude product waspurified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN inwater) to obtain 80 mg (54%) of the title compound. ¹H-NMR (400 MHz;CDCl₃): δ 1.24 (d, 3H), 2.55 (d, 3H), 4.26 (dd, 1H), 4.45 (dd, 1H),4.51-4.62 (m, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.60 (dd, 1H), 7.68 (d,1H), 7.79 (dd, 1H), 8.13 (d, 1H), 8.24 (d, 1H).

Example 101(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide

To a solution of 1,2,5-oxadiazole-3-carboxylic acid (66 mg, 0.58 mmol)in 5 ml of DCM were added anhydrous HOBt (88 mg, 0.65 mmol) andPS-carbodiimide (590 mg, 0.77 mmol). After 10 min(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg,0.38 mmol) was added and the reaction mixture was stirred at RTovernight. Resin was filtered and washed twice with DCM. Filtrate waswashed with 10% citric acid, 1 M NaHCO₃-solution, brine and water.Organic phase was dried over Na₂SO₄, filtered and evaporated to give 111mg (81%) of the title compound. ¹H-NMR (400 MHz; CDCl₃): δ 1.25 (d, 3H),4.25 (dd, 1H), 4.48 (dd, 1H), 4.58-4.70 (m, 1H), 6.66 (d, 1H), 7.51 (d,1H), 7.71 (dd, 1H), 7.83 (dd, 1H), 8.01 (dd, 1H), 8.31 (d, 1H), 8.65 (s,1H).

Example 102N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

To a cooled (0° C.) solution of sodium borohydride (12 mg, 0.32 mmol) in2 ml of dry EtOH was added(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamideof Example 99 (66 mg, 0.16 mmol) as a solution in 3 ml of dry EtOH.Reaction mixture was stirred at RT overnight before being quenched byadding some water and 0.5 M HCl until pH was acidic. Solvents wereevaporated and the evaporation residual was taken up in 5% MeOH in DCM,washed with 1 M NaHCO₃ solution and water. Organic phase was dried overNa₂SO₄, filtered and evaporated to yield 64 mg (96%) of the titlecompound. ¹H-NMR (400 MHz; CDCl₃/MeOD): δ 1.00 (t, 3H), 1.48-1.65 (m,5H), 4.29-4.43 (m, 3H), 4.94 (q, 1H), 6.59-6.62 (m, 2H), 7.52 (d, 1H),7.67-7.72 (m, 1H), 7.78-7.82 (m, 1H), 7.99-8.01 (m, 1H).

Example 103(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-methyl-1,2,4-oxadiazole-5-carboxamide

(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (219 mg,0.84 mmol) was coupled with 3-methyl-1,2,4-oxadiazole-5-carboxylic acidusing the method of Example 34(d). Crude product was suspended in MeCNand MeOH. Suspension was filtered to give 16 mg (5%) the title compoundas a colourless solid. Filtrate was purified by CombiFlash (column: C-18silica, eluent: 0-100% MeCN in water). Fractions containing the titlecompound were combined and suspended in MeCN. Suspension was filtered togive 9 mg (3%) the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.19 (d,3H), 2.44 (s, 3H), 4.34 (d, 2H), 4.39-4.53 (m, 1H), 6.95 (d, 1H), 7.84(d, 1H), 7.92 (dd, 1H), 7.98 (d, 1H), 8.06 (d, 1H), 9.42 (d, 1H).

Example 104N—((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamidea) (R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (3.00 g, 13.3 mmol) was reactedwith N-Boc-(R)-(+)-2-amino-1-butanol (2.76 g, 14.6 mmol) in the presenceof triphenylphosphine and DIAD using the method of Example 99. AfterBoc-deprotection 1.48 g (41%) of the title compound was obtained. ¹H-NMR(400 MHz; d6-DMSO): δ. 0.87-0.94 (m, 3H), 1.11-1.40 (m, 2H), 2.97-3.06(m, 1H), 4.01 (dd, 1H), 4.13 (dd, 1H), 4.68-4.84 (m, 1H), 6.96 (d, 1H),7.86 (d, 1H), 7.94 (dd, 1H), 7.97 (dd, 1H), 8.09-8.11 (m, 1H). MS [M+1]:m/z [274.8+1].

b)(R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamide

(R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (300 mg,1.1 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (202mg, 1.3 mmol) using the method of Example 34(d). Crude product waspurified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN inwater) to obtain 225 mg (50%) of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 0.90 (t, 3H), 1.43-1.65 (m, 2H), 2.49 (s, 3H), 4.22-4.41 (m,3H), 6.91 (d, 1H), 7.32 (s, 1H), 7.79 (d, 1H), 7.86-8.05 (m, 3H), 8.38(d, 1H), 14.1 (bs, 1H).

c)N—((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

(R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamide(225 mg, 0.55 mmol) was treated with sodium borohydride using the methodof Example 102. Thus, 192 mg (85%) of title compound was obtained.¹H-NMR (400 MHz; CDCl₃/MeOD): δ 1.00 (t, 3H), 1.46-1.67 (m, 5H),4.28-4.44 (m, 3H), 4.94 (q, 1H), 7.61 (m, 2H), 7.53 (d, 1H), 7.69 (d,1H), 7.80 (d, 1H), 8.00 (d, 1H).

Example 105(S)-3-acetyl-N-(1-(3-(4-cyano-3-(methylthio)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide(64 mg, 0.16 mmol) was placed into a microwave vial. DMF (1 ml) andsodium thiomethoxide (12.4 mg, 0.18 mmol) were added and the reactionmixture was heated in microwave reactor at 150° C. Sodium thiomethoxidewas added after 30, 30 and 20 min of heating (12.4 mg, 5.6 mg and 5.6mg, respectively). After total of 90 min of heating DMF was evaporated,and the evaporation residual was taken up in DCM and washed with water.Organic phase was dried over Na₂SO₄, filtered and evaporated. Thusobtained crude product was suspended in MeCN. Suspension was filtered togive 9 mg (14%) of the title compound as a colourless solid. Filtratewas purified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN inwater) to yield 13 mg (20%) of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 1.11-1.20 (m, 3H), 2.49 (s, 3H, overlap with DMSO) 2.57-2.64(m, 3H), 4.20-4.55 (m, 3H), 6.91 (s, 1H), 7.31 (s, 1H), 7.62-7.89 (m,4H), 8.47 (dd, 1H), 14.2 (d, 1H).

Example 106(S)-5-acetyl-N-(1-(3-(4-cyano-3-iodophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamidea) 2-nitro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile

To a solution of 4-chloro-2-nitrobenzonitrile (15 g, 82 mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(27.4 g, 99 mmol) in 300 ml of DMF were addedbis(triphenylphosphine)palladium (II) chloride (1.12 g; 1.64 mmol),sodium carbonate (22.7 g; 0.16 mol) and water (30 ml). The reactionmixture was heated at 90° C. for 4.5 h, cooled and poured into 500 ml ofwater. The water phase was extracted twice with EtOAc, and the combinedorganic fractions were washed with saturated NaHCO₃— solution and brine,dried over Na₂SO₄ and evaporated. The evaporation residual was suspendedto EtOH (100 ml) and the remaining solids were filtered to give 17.7 g(72%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.52-1.68 (m,3H), 1.78-1.87 (m, 1H), 1.91-2.00 (m, 1H), 2.31-2.47 (m, 1H), 3.67-3.76(m, 1H), 3.99-4.06 (m, 1H), 5.32 (dd, 1H), 6.84 (d, 1H), 7.69 (d, 1H),8.13 (dd, 1H), 8.32 (d, 1H), 8.60 (d, 1H).

b) 2-nitro-4-(1H-pyrazol-5-yl)benzonitrile

To a solution of2-nitro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-benzonitrile(17.7 g, 59 mmol) in EtOH (440 ml) was added 44 ml of concentrated HCl.The reaction mixture was stirred at RT for 1.5 h. The mixture was pouredinto water (1 l), and 2 M NaOH-solution was added until pH was 12. Thusresulting precipitate was filtered, washed with water and dried to give11.7 g (92%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 7.09(d, 1H), 7.91 (d, 1H), 8.20 (d, 1H), 8.37 (dd, 1H), 8.73 (d, 1H), 13.4(bs, 1H).

c) (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile

(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile wasprepared from 2-nitro-4-(1H-pyrazol-5-yl)benzonitrile (2.0 g, 9.3 mmol)using the method of Example 34(d). Thus, 1.6 g (71%) of the titlecompound was obtained. ¹H-NMR (400 MHz; d6-DMSO): δ 0.98 (d, 3H),3.25-3.33 (m, 1H), 4.01-4.11 (m, 2H), 7.08 (d, 1H), 7.90 (d, 1H), 8.18(d, 1H), 8.34 (dd, 1H), 8.69 (d, 1H).

d)(S)-3-acetyl-N-(1-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (400 mg,1.48 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (250mg, 1.62 mmol) using the method of Example 34(d). Crude product waspurified by CombiFlash (column: silica, eluent: 0-10% MeOH in DCM) toyield 295 mg (49%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ1.18 (d, 3H), 2.49 (s, 3H), 4.26-4.55 (m, 3H), 7.04 (d, 1H), 7.30 (s,1H), 7.86 (d, 1H), 8.18 (d, 1H), 8.31 (d, 1H), 8.50 (d, 1H), 8.63 (s,1H), 14.1 (bs, 1H).

e)(S)-3-acetyl-N-(1-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

Tin(II) chloride dihydrate (490 mg, 2.17 mmol) was added to a cooled (0°C.) solution of(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (295 mg,0.72 mmol) in conc. HCl (2 ml). Reaction mixture was stirred at RTovernight. Small volume of 1 M NaOH was added until precipitate wasformed. Solids were filtered, washed with water and dried to yield 0.263g (96 5) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.14 (d,3H), 2.50 (s, 3H), 4.27 (m, 2H), 4.45 (m, 1H), 6.62 (d, 1H), 7.01 (dd,1H), 7.27 (d, 1H), 7.32 (s, 1H), 7.38 (d, 1H), 7.75 (d, 1H), 8.51 (d,1H).

f)(S)-5-acetyl-N-(1-(3-(4-cyano-3-iodophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide

Sodium nitrite (50 mg, 0.73 mmol) in 1 ml of water was added slowly to asolution of(S)-3-acetyl-N-(1-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide(250 mg, 0.66 mmol) in water (2 ml), sulfuric acid (71 μl, 1.33 mmol)and MeCN (3 ml) at 0° C. After 15 min potassium iodide (0.22 g, 1.32mmol) in 1 ml of water was added. Reaction mixture was stirred at RT for2 h and then poured into 10 ml of water. Thus resulting precipitate wasfiltered and washed with 10% sodium bisulfite solution and water. Crudeproduct was purified by CombiFlash (column: silica, eluent: 3-10% MeOHin DCM) to yield 75 mg (23%) of the title compound. ¹H-NMR (400 MHz;MeOD): δ 1.27 (d, 3H), 2.55 (s, 3H), 4.35 (m, 1H), 4.39 (m, 1H), 4.57(m, 1H), 6.63 (d, 1H), 7.28 (br s, 1H), 7.42 (s, 1H), 7.57 (d, 1H), 7.66(d, 1H), 7.93 (br s, 1H), 8.35 (s, 1H).

Example 107N—((S)-1-(3-(4-cyano-3-iodophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

N—((S)-1-(3-(4-cyano-3-iodophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide(65 mg, 0.13 mmol) was treated with sodium borohydride using the methodof Example 102. Crude product was suspended in small volume of MeCN andthe remaining solids were filtered to yield 19 mg (29%) of the titlecompound. ¹H-NMR (400 MHz; MeOD/CDCl3): δ 1.05 (d, 3H), 1.33 (d, 3H),4.12-4.19 (m, 1H), 4.28-4.40 (m, 1H), 4.70-4.79 (m, 1H), 6.38-6.48 (m,2H), 7.36-7.40 (m, 1H), 7.44-7.45 (m, 1H), 7.69-7.75 (m, 1H), 8.18-8.82(m, 1H).

Example 108(R)-3-acetyl-N-(1-(3-(6-cyano-5-nitropyridin-3-yl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamidea)3-nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinonitrile

To a solution of 5-bromo-3-nitropyridine-2-carbonitrile (2.00 g, 8.77mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.68 g, 9.65 mmol) in 10 ml of ethylene glycol dimethyl ether wereadded bis(triphenylphosphine)palladium(II) chloride (0.31 g; 0.44 mmol)and 9 ml of 2 M sodium carbonate-solution. The reaction mixture washeated at 50° C. for 2 h. Cooled reaction mixture was filtered, thesolids were washed with water and dried in vacuum to give 2.77 g (105%)of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.50-1.66 (m, 3H),1.81-2.04 (m, 2H), 2.29-2.47 (m, 1H), 3.66-3.79 (m, 1H), 3.97-4.07 (m,1H), 5.37 (dd, 1H), 6.99 (d, 1H), 7.74 (d, 1H), 8.92 (s, 1H), 9.25 (s,1H).

b) 3-nitro-5-(1H-pyrazol-5-yl)picolinonitrile

3-Nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinonitrile(8.77 mmol) was dissolved in 10% HCl (g) in EtOH (15 ml) and stirred atRT overnight. 20 ml of water was added to the reaction mixture, followedby addition of sat. sodium bicarbonate solution until pH was neutral.Thus resulting precipitate was filtered, washed with water and dried invacuum to yield 1.76 g (93%) of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 7.22 (m, 1H), 7.98 (m, 1H), 8.99 (d, 1H), 9.50 (d, 1H), 13.5(bs, 1H).

c) (R)-5-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-3-nitropicolinonitrile

(R)-5-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-3-nitropicolinonitrile wasprepared from 3-nitro-5-(1H-pyrazol-5-yl)picolinonitrile (0.88 g, 4.9mmol) and (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (0.86 g, 4.9mmol) using the method of Example 34(d). Thus, 0.62 g (56%) of the titlecompound was obtained. m/z [273.3+1].

d)(R)-3-acetyl-N-(1-(3-(6-cyano-5-nitropyridin-3-yl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

(R)-5-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-3-nitropicolinonitrile (0.62g, 1.14 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid(0.39 g, 2.50 mmol) using the method of Example 34(d). Crude product waspurified twice by CombiFlash (1^(st) column: silica, eluent: 0-10% MeOHin DCM; 2^(nd) column: C-18, eluent: 0-100% MeCN in water) to yield 86mg (19%) of the title compound. ¹H-NMR (400 MHz; CDCl₃): δ 1.23 (d, 3H),2.56 (s, 3H), 4.33 (dd, 1H), 4.55 (dd, 1H), 4.58-4.67 (m, 1H), 6.83-6.86(m, 1H), 7.29-7.31 (broad s, 1H), 7.65 (d, 1H), 8.91-8.94 (broad s, 1H),9.64-9.67 (m, 1H).

Example 109(S)-3-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamidea) (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (0.91 g, 3.80 mmol) was reactedwith N-Boc-(S)-1-amino-2-propanol (1.00 g, 5.71 mmol) in the presence oftriphenyl-phosphine and DIAD using the method of Example 99. AfterBoc-deprotection 0.30 g (30%) of the title compound was obtained. ¹H-NMR(400 MHz; d6-DMSO): δ 1.43 (d, 3H), 2.91-3.40 (m 1H), 4.29-4.39 (m, 1H),4.71-4.85 (m, 1H), 7.97 (d, 1H), 7.89 (d, 1H), 7.96 (d, 1H), 7.97 (d,1H), 8.11 (dd, 1H). m/z [260.7+1].

b)(S)-3-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide

(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (217mg, 0.416 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid(128 mg, 0.832 mmol) using the method of Example 34(d). Crude productwas purified by CombiFlash (column: C-18, eluent: 0-100% MeCN in water)to yield 30 mg (18%) of the title compound. ¹H-NMR (400 MHz; CDCl₃): δ1.62 (d, 3H), 2.55 (s, 3H), 3.74-3.83 (m, 1H), 3.90-3.99 (m, 1H),4.58-4.69 (m, 1H), 6.61 (d, 1H), 7.29 (bs, 1H), 7.50 (d, 1H), 7.68 (d,1H), 7.77 (dd, 1H), 8.09 (s, 1H), 11.1 (bs, 1H).

Example 110(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-methyl-1H-imidazole-4-carboxamide

(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.77 mmol) was coupled with 1-methyl-1H-imidazole-4-carboxylic acid (145mg, 1.15 mmol) using the method of Example 34(d). Crude product waspurified twice by CombiFlash (1^(st) column: C-18, eluent: 0-100% MeCNin water; 2^(nd) column: silica, eluent 100% DCM) to yield a total of121 mg (43%) of the title compound. ¹H-NMR (400 MHz; CDCl₃): δ 1.22 (d,3H), 3.74 (s, 3H), 4.27 (dd, 1H), 4.41 (dd, 1H), 4.50-4.62 (m, 1H), 6.61(d, 1H), 7.43 (d, 1H), 7.48 (d, 1H), 7.50 (d, 1H), 7.66 (d, 1H), 7.78(dd, 1H), 7.86 (d, 1H), 8.17 (d, 1H).

Example 111(R)-3-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamidea) (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (1.45 g, 7.13 mmol) was reactedwith N-Boc-(R)-1-amino-2-propanol (1.50 g, 8.56 mmol) in the presence oftri-phenylphosphine and DIAD using the method of Example 99. AfterBoc-deprotection 843 mg (45%) of the title compound was obtained. ¹H-NMR(400 MHz; d6-DMSO): δ 1.43 (d, 3H), 3.53-3.67 (m, 1H), 4.29-4.38 (m,1H), 4.69-4.83 (m, 1H), 6.96 (d, 1H), 7.89 (d, 1H), 7.95 (dd, 1H), 7.97(dd, 1H), 8.10-8.12 (m, 1H). m/z [260.7+1].

b)(R)-3-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide

(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(1.29 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (259mg, 1.68 mmol) using the method of Example 34(d). Crude product waspurified twice by CombiFlash (1^(st) column: C-18, eluent: 0-100% MeCNin water; 2^(nd) column: silica, eluent: 0-7% MeOH in DCM) to yield 288mg (56%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.49 (d,3H), 2.48 (s, 3H), 3.56-3.73 (m, 2H), 4.60-4.75 (m, 1H), 6.94 (d, 1H),7.27 (bs, 1H), 7.87 (d, 1H), 7.91-8.01 (m, 2H), 8.08 (dd, 1H), 8.58 (bs,1H), 14.2 (bs, 1H).

Example 112N—((R)-2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

(R)-3-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide(100 mg, 0.25 mmol) was treated with sodium borohydride using the methodof Example 102. Thus, 87 mg (87%) of the title compound was obtained.¹H-NMR (400 MHz; d6-DMSO): δ 1.37 (d, 3H), 1.46 (d, 3H), 3.52-3.72 (m,2H), 4.63-4.84 (m, 2H), 5.40 (bs, 1H), 6.42 (bs, 1H), 6.95 (d, 1H), 7.87(d, 1H), 7.99 (s, 2H), 8.09-8.22 (m, 2H), 13.0 (bs, 1H).

Example 113(R)-2-(aminomethyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-1H-imidazole-5-carboxamidea) (R)-tert-butyl(5-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-imidazol-2-yl)methylcarbamate

(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (108 mg,0.42 mmol) was coupled with2-(tert-Butoxycarbonylaminomethyl)-1H-imidazole-5-carboxylic acid (100mg, 0.42 mmol) using the method of Example 34(d). After extraction aquantitative yield of the title compound was obtained.

b)(R)-2-(aminomethyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-imidazole-5-carboxamide

(R)-tert-butyl(5-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-imidazol-2-yl)methylcarbamate(0.42 mmol) was stirred with 10% HCl (g) in EtOH (30 ml) overnight.Solvent was evaporated and the residue was taken up in water (50 ml),washed with DCM (3×30 ml) and made strongly alkaline by adding 2 M NaOHsolution. The water phase was extracted with DCM (3×50 ml) and combinedorganic phases were dried over Na₂SO₄ and evaporated to yield 104 mg(65%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.08 (d, 3H),3.73 (s, 2H), 4.27 (dd, 1H), 4.32-4.48 (m, 2H), 6.95 (d, 1H), 7.44 (s,1H), 7.83 (d, 1H), 7.94-8.03 (m, 2H), 8.07 (d, 1H), 8.10 (m, 1H).

Example 114(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

The title compound was prepared as described in Example 34(d), startingfrom 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid (0.166g, 0.997 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g,0.767 mmol). The product was purified with flash-chromatography. Yield56.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.09 (d, 3H), 1.74-1.82 (m, 2H),1.94-2.03 (m, 2H), 2.71-2.78 (m, 2H), 4.11 (t, 2H), 4.27 (dd, 1H), 4.36(dd, 1H), 4.39-4.49 (m, 1H), 6.30 (s, 1H), 6.95 (d, 1H), 7.82 (d, 1H),7.96-8.01 (m, 2H), 8.08-8.11 (m, 1H), 8.16 (d, 1H).

Example 115(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamidea) Ethyl 2-(1H-imidazol-4-yl)thiazole-4-carboxylate

1H-Imidazole-4-carbothioamide (1 g, 7.86 mmol) and ethyl bromopyruvate(0.987 ml, 7.86 mmol) were dissolved in ethanol (20 ml). The resultingmixture was refluxed for 1.5 hours. The mixture was kept at 0° C. for anhour and filtered. Both the filtered precipitate and filtrate containedthe product and both were evaporated. The filtrate was triturated twicefrom ethanol. In the end all precipitates were combined. LC-MS:[M+1]=224.25.

b) 2-(1H-imidazol-4-yl)thiazole-4-carboxylic Acid

Ethyl 2-(1H-imidazol-4-yl)thiazole-4-carboxylate (1.5 g, 6.72 mmol) wasdissolved in THF (10 ml). Into the suspension, lithium hydroxydemonohydrate 1M solution (13.44 ml, 13.44 mmol) was added and theresulting mixture was stirred for 4 h. Then 3.36 ml of lithium hydroxydemonohydrate 1M solution was added and the mixture was stirred foranother hour. The mixture was evaporated, 10 ml of water added and thepH was adjusted to 1 with concentrated HCl. The precipitate wasfiltered. Both the filtrate and filtered precipitate contained theproduct. The filtrate was dissolved in toluene and evaporated twice.LC-MS: [M+1]=196.20.

c)(S)—N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1H-imidazol-4-yl)thiazole-4-carboxamide

The title compound was prepared as described in Example 34(d), startingfrom 2-(1H-imidazol-4-yl)thiazole-4-carboxylic acid (0.097 g, 0.496mmol) (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile(0.1 g, 0.381 mmol). The product was purified with flash-chromatography.Yield 44.8%. 1H-NMR (400 MHz; CDCl₃): δ 1.25 (d, 3H), 4.32 (dd, 1H),4.42 (dd, 1H), 4.57-4.68 (m, 1H), 6.58 (s, 1H), 7.42 (s, 1H), 7.44 (s,1H), 7.51 (d, 1H), 7.65 (d, 1H), 7.77 (d, 1H), 7.84 (d, 1H), 7.98 (s,1H), 11.72 (bs, 1H).

Example 116(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamidea) 4-bromo-3-chloro-5-fluoroaniline

To a cooled (0° C.) solution of 3-chloro-5-fluoroaniline (5.0 g, 33mmol) in MeCN (50 ml) was added a suspension of N-bromosuccinimide (5.9g, 33 mmol) in MeCN (10 ml). After being stirred for 2 h at RT thereaction was quenched by adding 10% NaHSO₃ (50 ml). The mixture wasconcentrated to about half of the volume, diluted with water (50 ml) andextracted with EtOAc (3×50 ml). Combined organic phases were dried overNa₂SO₄ and evaporated to give crude product, which was purified byCombiFlash (column: silica, eluent: 0-100% EtOAc in heptane) to yield5.5 g (74%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 5.88(bs, 2H), 6.45 (dd, 1H), 6.64 (m, 1H).

b) 4-amino-2-chloro-6-fluorobenzonitrile

A mixture of 4-bromo-3-chloro-5-fluoroaniline (2.08 g, 9.27 mmol) andcopper(I)cyanide (0.83 g, 9.27 mmol) in DMF (15 ml) was heated inmicrowave reactor at 190° C. for 1 h. Reaction mixture was poured into12% ammonium hydroxide (200 ml) and stirred for 30 min. Thus formedprecipitate was filtered, washed with water and dried in vacuum toobtain 1.21 g (77%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ6.44 (dd, 1H), 6.60 (m, 1H), 6.86 (bs, 2H).

c) 2-chloro-6-fluoro-4-iodobenzonitrile

To a cooled (0° C.) solution of 4-amino-2-chloro-6-fluorobenzonitrile(3.55 g, 20.8 mmol), sulfuric acid (3.33 ml, 62.4 mmol), water (30 ml)and MeCN (100 ml) was added slowly a solution of sodium nitrite (1.58 g,22.9 mmol) in water (10 ml). A solution of potassium iodide (6.91 g,41.6 mmol) in water (10 ml) was added slowly while maintainingtemperature of the reaction mixture below 10° C. After being stirred atRT for 2 h, the reaction was quenched by adding water (100 ml) andconcentrating the mixture to about half of the original volume. Themixture was extracted with DCM (3×150 ml), and combined organicfractions were dried over Na₂SO₄ and evaporated to yield 4.77 g, (81%)of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 8.06 (dd, 1H), 8.08(m, 1H).

d)2-chloro-6-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-benzonitrile

To a solution of 2-chloro-6-fluoro-4-iodobenzonitrile (5.75 g, 20.4mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(7.39 g, 26.6 mmol) in THF (60 ml) was addedbis(triphenylphosphine)-palladium(II) chloride (0.717 g, 1.02 mmol),sodium carbonate (5.20 g, 49.0 mmol) and water (20 ml). Reaction mixturewas heated at 60° C. for 2 h, concentrated to ¼ of the volume, dilutedwith water (40 ml) and stirred at RT for 1 h. Thus resulting solid wasfiltered and suspended in EtOH (30 ml). Suspension was stirred at −10°C. for 1 h, precipitate was filtered and washed with EtOH to yield 2.90g (46%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.49-1.72(m, 3H), 1.78-2.03 (m, 2H), 2.29-2.44 (m, 1H), 3.56-3.68 (m, 1H),3.93-4.03 (m, 1H), 5.36 (dd, 1H), 6.78 (d, 1H), 7.66 (d, 1H), 7.73 (dd,1H), 7.81 (m, 1H).

e) 2-chloro-6-fluoro-4-(1H-pyrazol-5-yl)benzonitrile

2-Chloro-6-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile(1.09 g, 3.55 mmol) was stirred with 10% HCl (g)/EtOH-solution (50 ml)at room temperature for 1 h. Reaction mixture was poured into water (50ml) and made slightly alkaline with saturated NaHCO₃ solution. Thusresulting precipitate was filtered, washed with water and dried invacuum to obtain 0.74 g (94%) of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 7.06 (d, 1H), 7.94 (dd, 1H), 8.05 (m, 1H), 13.4 (bs, 1H).

f)(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile

2-Chloro-6-fluoro-4-(1H-pyrazol-5-yl)benzonitrile (0.74 g, 3.3 mmol) wasreacted with (S)-(−)-2-tert-butoxycarbonylamino)-1-propanol (0.88 g, 5.0mmol) in the presence of triphenylphosphine and DIAD using the method ofExample 99. After Boc-deprotection 0.45 g (49%) of the title compoundwas obtained. ¹H-NMR (400 MHz; d6-DMSO): δ 0.95 (d, 3H), 3.17-3.28 (m,1H), 4.01 (dd, 2H), 7.03 (d, 1H), 7.85-7.91 (m, 2H), 7.99 (m, 1H).

g)(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.22 g, 0.55 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylicacid (0.17 g, 1.11 mmol) using the method of Example 34(d). Crudeproduct was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN inwater) to yield 47 mg (21%) of the title compound. ¹H-NMR (400 MHz;MeOD): δ 1.28 (d, 3H), 2.51 (s, 3H), 4.31 (dd, 1H), 4.41 (dd, 1H),4.52-4.61 (m, 1H), 6.79 (d, 1H), 7.23 (s, 1H), 7.67 (d, 1H), 7.70 (d,1H), 7.83 (m, 1H).

Example 117(R)-3-acetyl-N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propyl)-1H-pyrazole-5-carboxamidea)(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile

N-t-BOC—(R)-1-Amino-2-propanol (3.22 g, 18.4 mmol) andtriphenylphosphine (4.82 g, 18.4 mmol) were dissolved in EtOAc (10 ml)and added to a solution of2-chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile (2.00 g, 9.2 mmol) inEtOAc (20 ml). Reaction mixture was cooled down to 0° C. and DIAD (3.62ml, 18.4 mmol) was added slowly by syringe. After 20 h of reaction timeat RT, water (10 ml) and conc. HCl (5.58 ml, 184 mmol) were added, andthe reaction was stirred another 20 h. Reaction mixture was diluted withwater, washed with DCM, and the organic phase was extracted twice withdiluted HCl. Combined water phases were washed twice with DCM, madealkaline (pH 12) by adding 50% NaOH solution, and extracted twice withDCM. Combined organic phases were dried over Na₂SO₄ and evaporated toyield 0.74 g (29%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ1.43 (d, 3H), 2.57 (s, 3H), 4.29-4.38 (m, 1H), 4.70-4.85 (m, 2H), 6.63(d, 1H), 7.69 (dd, 1H), 7.82 (dd, 1H), 7.89 (d, 1H). m/z [274.8+1].

b)(R)-3-acetyl-N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide

(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(300 mg, 1.09 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylicacid (202 mg, 1.31 mmol) using the method of Example 34(d). Crudeproduct was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN inwater) to yield 83 mg (19%) of the title compound. ¹H-NMR (400 MHz;CDCl₃): δ 1.62 (d, 3H), 2.52-2.58 (m, 6H), 3.79 (dd, 1H), 3.91 (dd, 1H),4.60-4.71 (m, 1H), 6.92 (d, 1H), 7.25 (s, 1H), 7.27-7.29 (m, 1H), 7.52(d, 1H), 7.54-7.60 (m, 2H).

Example 118(R)—N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-1-methyl-1H-imidazole-4-carboxamide

(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (300mg, 1.15 mmol) was coupled with 1-methyl-1H-imidazole-4-carboxylic acid(174 mg, 1.38 mmol) using the method of Example 34(d). Crude product waspurified by CombiFlash (column: C-18, eluent: 0-100% MeCN in water) toyield 61 mg (14%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ1.45 (d, 3H), 3.52-3.72 (m, 4H), 3.67 (s, 3H), 4.63-4.75 (m, 1H), 6.95(d, 1H), 7.62 (dd, 1H), 7.89 (d, 1H), 7.99 (s, 1H), 8.00 (s, 1H), 8.10(t, 1H), 8.18 (t, 1H).

Example 119(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methyl-1,2,4-oxadiazole-3-carboxamide

(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (573 mg,2.20 mmol) was coupled with 5-methyl-1,2,4-oxadiazole-3-carboxylic acid(338 mg, 2.64 mmol) using the method of Example 34(d). Crude product waspurified by CombiFlash (column: silica, eluent: 0-100% EtOAc in heptane)to yield 125 mg (15%) of the title compound. ¹H-NMR (400 MHz; d6-DMSO):δ 1.61 (d, 3H), 2.66 (s, 3H), 4.28-4.39 (m, 2H), 4.41-4.53 (m, 1H), 6.95(d, 1H), 6.83 (d, 1H), 7.94 (dd, 1H), 7.99 (dd, 1H), 8.09 (m, 1H), 9.02(d, 1H).

Example 120(S)-5-((1H-imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-2-carboxamidea) Ethyl 5-(bromomethyl)thiazole-2-carboxylate

A mixture of ethyl thiooxamate (3.00 g, 22.5 mmol) and1,3-dibromoacetone (4.86 g, 22.5 mmol) in dry EtOH (30 ml) was refluxedfor 3.5 h and stirred at RT for 20 h. Solvent was evaporated and theresidue was taken up in water and extracted twice with DCM to obtaincrude product, which was purified by CombiFlash (column: silica, eluent:10-100% EtOAc in heptane) to yield 842 mg (15%) of the title compound.¹H-NMR (400 MHz; d6-DMSO): δ 1.34 (t, 3H), 4.39 (q, 2H), 4.83 (s, 2H),8.16-8.17 (m, 1H).

b) Ethyl 5-((1H-imidazol-1-yl)methyl)thiazole-2-carboxylate

To a cooled (0 C) suspension of sodium hydride (60% in oil, 82 mg, 2.05mmol) in dry DMF (2 ml) was added imidazole (93 mg, 1.37 mmol) as asolution in dry DMF (0.5 ml). Mixture was stirred at RT 45 min, cooledto 0° C. followed by addition of ethyl5-(bromomethyl)thiazole-2-carboxylate (342 mg, 1.37 mmol) dissolved indry DMF (2 ml). After being stirred at RT for 20 h, the reaction mixturewas evaporated and the residue was taken up in DCM and washed twice withsaturated NaCl solution. Thus, 143 mg (44%) of the title compound wasobtained. ¹H-NMR (400 MHz; d6-DMSO): δ 1.32 (t, 3H), 4.37 (q, 2H), 5.39(s, 2H), 6.91 (s, 1H), 7.20 (s, 1H), 7.75 (s, 1H), 7.93 (s, 1H).

c) 5-((1H-imidazol-1-yl)methyl)thiazole-2-carboxylic Acid

A solution of ethyl 5-((1H-imidazol-1-yl)methyl)thiazole-2-carboxylate(143 mg, 0.60 mmol) and 1 M LiOH solution (1.2 ml, 1.2 mmol) in THF (2ml) and MeOH (1 ml) was stirred at RT for 1.5 h. Some 1 M HCl was addeduntil pH of the mixture was about 8. Solvents were evaporated and thusobtained crude product was used as such in the next synthesis step.¹H-NMR (400 MHz; d6-DMSO): δ 5.28 (s, 2H), 6.92 (s, 1H), 7.22 (s, 1H),7.54 (s, 1H), 7.79 (s, 1H).

d)(S)-5-((1H-imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-2-carboxamide

(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (157 mg,0.60 mmol) was coupled with5-((1H-imidazol-1-yl)methyl)thiazole-2-carboxylic acid (0.60 mmol) usingthe method of Example 34(d). Crude product was purified twice byCombiFlash (1^(st) column: C-18, eluent: 0-100% MeCN in water; 2^(nd)column: silica, eluent: 0-8% MeOH in DCM) to yield 13 mg (5%) of thetitle compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 2H), 4.29-4.52 (m,3H), 5.36 (s, 2H), 6.92 (s, 1H), 6.94 (dd, 1H), 7.22 (s, 1H), 7.71 (s,1H), 7.75 (s, 1H), 7.83 (d, 1H), 7.90 (dd, 1H), 7.96 (d, 1H), 8.04 (d,1H), 8.83 (d, 1H).

Example 121(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)imidazo[1,2-a]pyrazine-2-carboxamide

The title compound was prepared as described in Example 34(d), startingfrom imidazo[1,2-a]pyrazine-2-carboxylic acid (0.163 g, 0.997 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g,0.767 mmol). The product was purified with flash-chromatography. Yield90%. 1H-NMR (400 MHz; CDCl₃): δ 1.18 (d, 3H), 4.35 (dd, 1H), 4.43 (dd,1H), 4.47-4.57 (m, 1H), 6.93 (d, 1H), 7.85 (d, 1H), 7.94-8.00 (m, 3H),8.03-8.06 (m, 1H), 8.47 (d, 1H), 8.60 (dd, 1H), 8.73 (d, 1H), 9.14-9.16(m, 1H).

Example 122(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxamide

The title compound was prepared as described in Example 34(d), startingfrom 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (0.127g, 0.767 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g,0.767 mmol). The product was purified by flash-chromatography. Yield55.5%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 1.66-1.75 (m, 2H),1.85-1.95 (m, 2H), 2.87 (t, 2H), 4.02 (t, 2H), 4.22-4.23 (m, 2H),4.32-4.42 (m, 1H), 6.94 (d, 1H), 7.72 (d, 1H), 7.80 (d, 1H), 7.83 (s,1H), 7.91 (dd, 1H), 7.97 (d, 1H), 8.06 (d, 1H).

Example 123(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide

(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from5-acetylisoxazole-3-carboxylic acid (2.142 g, 13.81 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3 g,2.142 g). The product was purified by Flash-chromatography with yield of30.5%. 1H-NMR (400 MHz; CDCl₃): δ 1.25 (d, 3H), 2.66 (s, 3H), 4.26 (dd,1H), 4.47 (dd, 1H), 4.56-4.66 (m, 1H), 4.65 (d, 1H), 7.30 (s, 1H), 7.50(d, 1H), 7.71 (d, 1H), 7.84 (dd, 1H), 7.08 (d, 1H), 7.17 (d, 1H).

Example 124N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)isoxazole-3-carboxamide

N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from5-(1-hydroxyethyl)isoxazole-3-carboxylic acid (2.170 g, 13.81 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3 g,11.51 mmol). The product was purified by Flash-chromatography with yieldof 46.1%. 1H-NMR (400 MHz; CDCl₃): δ 1.23 (d, 3H), 1.62 (d, 3H), 2.30(s, 1H), 4.26 (dd, 1H), 4.43 (dd, 1H), 4.53-4.64 (m, 1H), 5.06 (q, 1H),6.63 (d, 1H), 6.64 (d, 1H), 7.48 (d, 1H), 7.69 (d, 1H), 7.84 (dd, 1H),7.87 (d, 1H), 8.05 (d, 1H).

Example 125(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-bromo-1,3-thiazole-4-carboxylic acid (0.957 g, 4.60 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1 g,3.84 mmol). Yield 62.7%. 1H-NMR (400 MHz; CDCl₃): δ 1.32 (d, 3H), 4.36(dd, 1H), 4.46 (dd, 1H), 4.58-4.63 (m, 1H), 6.63 (d, 1H), 7.51 (d, 1H),7.65 (d, 1H), 7.70 (d, 1H), 7.76 (dd, 1H), 7.93 (d, 1H), 7.40 (s, 1H).

Example 1261-(3-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)isoxazol-5-yl)ethylAcetate

N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)isoxazole-3-carboxamide(28 mg, 0.070 mmol) and DMAP (0.864 mg, 7.00 μmol) were dissolved inpyridine under nitrogen atmosphere. The reaction mixture was cooled to0° C., acetic anhydride (7.51 mg, 0.074 mmol) was added and the reactionmixture stirred for 2 h. The solvent was evaporated. Yield 82%. 1H-NMR(400 MHz; CDCl₃): δ 1.23 (d, 3H), δ 1.64 (d, 3H), 2.11 (s, 3H), 4.25(dd, 1H), 4.43 (dd, 1H), 4.54-4.63 (m, 1H), 6.05 (q, 1H), 6.63 (d, 1H),6.65 (d, 1H), 7.48 (d, 1H), 7.70 (d, 1H), 7.84 (dd, 1H), 7.89 (d, 1H),8.06 (d, 1H).

Example 127(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyridin-4-yl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-(4-pyridyl)thiazole-4-carboxylic acid (0.190 g, 0.921 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g,0.767 mmol). The product triturated using diethyl ether. Yield 47.5%.1H-NMR (400 MHz; MeOD): δ 1.33 (d, 3H), 4.40 (dd, 1H), 4.47 (dd, 1H),4.60-4.65 (m, 1H), 6.77 (d, 1H), 7.63 (d, 1H), 7.74 (d, 1H), 7.82 (dd,1H), 7.93 (d, 1H), 8.00 (dd, 1H), 8.01 (dd, 1H), 8.30 (s, 1H), 8.65 (dd,1H), 8.66 (dd, 1H).

Example 128(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-morpholinothiazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-morpholinothiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-morpholino-1,3-thiazole-4-carboxylic acid (0.454 g, 2.117 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.5 g,1.764 mmol. The product was purified by Flash-chromatography. Yield5.48%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 3.38-3.43 (m, 4H),3.67-3.72 (m, 4H), 4.27-4.45 (m, 3H), 6.95 (d, 1H), 7.40 (s, 1H), 7.83(d, 1H), 7.92 (dd, 1H), 7.97 (d, 1H), 7.98 (dd, 1H), 8.06 (d, 1H).

Example 129(S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide

(S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-amino-1,3-oxazole-4-carboxylic acid (0.037 g, 0.288 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.05 g,0.192 mmol). Yield 35.7%. 1H-NMR (400 MHz; MeOD): δ 1.23 (d, 3H), 4.30(dd, 1H), 4.37 (dd, 1H), 4.46-4.54 (m, 1H), 6.77 (d, 1H), 7.65 (s, 1H),7.69 (d, 1H), 7.79 (dd, 1H), 7.91 (dd, 1H), 8.05 (dd, 1H).

Example 130(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(piperidin-4-yl)thiazole-4-carboxamidea) (S)-tert-butyl4-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazol-2-yl)piperidine-1-carboxylate

(S)-tert-butyl4-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazol-2-yl)piperidine-1-carboxylatewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (400 mg,1.534 mmol) and2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid(479 mg, 1.534 mmol). The product was purified twice byFlash-chromatography. Yield 33.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d,3H), 1.41 (s, 9H), 1.49-1.64 (m, 2H), 1.98-2.08 (m, 2H), 2.89 (bs, 2H),3.15-3.27 (m, 1H), 3.96-4.09 (m, 2H), 4.29-4.52 (m, 3H), 6.96 (s, 1H),7.84 (d, 1H), 7.92 (dd, 1H), 7.97 (dd, 1H), 8.06 (dd, 1H), 8.10 (s, 1H),8.28 (d, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(piperidin-4-yl)thiazole-4-carboxamide

(S)-tert-butyl4-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazol-2-yl)piperidine-1-carboxylate(0.3 g, 0.540 mmol) and TFA (0.768 g, 6.73 mmol) was dissolved in amixture of DCM/TFA/H₂O and stirred overnight. The reaction mixture wasdiluted with DCM, washed with saturated Na₂CO₃ and with water. Theorganic layer was evaporated. Yield 82%. 1H-NMR (400 MHz; DMSO-d6): δ1.24 (d, 3H), 1.52 (dd, 1H), 1.58 (dd, 1H), 1.91-1.97 (m, 2H), 2.54-2.62(m, 2H), 2.97-3.03 (d, 2H), 3.04-3.11 (m, 1H), 4.33 (dd, 1H), 4.41 (dd,1H), 4.44-4.51 (m, 1H), 6.96 (d, 1H), 7.85 (d, 1H), 7.94 (dd, 1H), 7.99(d, 1H), 8.07 (d, 1H), 8.08 (s, 1H), 8.28 (d, 1H).

Example 131(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamidea) 2-(Methylamino)thiazole-4-carboxylic Acid

Ethyl 2-methylamino-1,3-thiazole-4-carboxylate (300 mg, 1.611 mmol) wasdissolved in THF/water mixture and 1M lithium hydroxide (3.22 ml, 3.22mmol) was added. The reaction mixture was stirred at RT for 3 hours, pHwas adjusted to acidic and the mixture was evaporated to dryness toyield the title compound. 1H-NMR (400 MHz; DMSO-d6): δ 2.84 (s, 3H),7.46 (s, 1H), 7.90 (bs, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methyl-amino)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.389 g,1.343 mmol) and 2-(methylamino)thiazole-4-carboxylic acid (255 mg, 1.612mmol). The product was purified by Flash-chromatography and trituratedusing diethyl ether. Yield 8.28%. 1H-NMR (400 MHz; DMSO-d6): δ 1.21 (d,3H), 2.85 (d, 3H), 4.28-4.43 (m, 3H), 6.96 (d, 1H), 7.18 (s, 1H), 7.59(q, 1H), 7.84 (d, 1H), 7.91 (d, 1H), 7.95-7.96 (m, 2H), 8.08 (dd, 1H).

Example 132(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-morpholinothiazole-4-carboxamide

(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-morpholinothiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-morpholino-1,3-thiazole-4-carboxylic acid (0.229 g, 1.070 mmol) and(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.25 g,0.892 mmol). The product was purified by Flash-chromatography andtriturated using diethyl ether. Yield 4.91%. 1H-NMR (400 MHz; DMSO-d6):δ 1.23 (d, 3H), 3.38-342 (m, 4H), 3.67-3.71 (m, 4H), 4.28-4.45 (m, 3H),6.95 (d, 1H), 7.39 (s, 1H), 7.83 (d, 1H), 7.92 (dd, 1H), 7.96 (d, 1H),7.98 (dd, 1H), 8.06 (d, 1H).

Example 133(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyridin-3-yl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-(3-pyridyl)-1,3-thiazole-4-carboxylic acid (0.285 g, 1.381 mmol) and(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.3 g,1.151 mmol). The product was purified by triturated using DCM. Yield1.065%. 1H-NMR (400 MHz; CDCl₃): δ 1.31 (d, 3H), 4.34 (dd, 1H), 4.48(dd, 1H), 4.60-470 (m, 1H), 6.63 (d, 1H), 7.37 (dd, 1H), 7.50-7.54 (m,2H), 7.80 (dd, 1H), 7.88 (d, 1H), 7.98 (d, 1H), 8.13-8.18 (m, 2H), 8.73(dd, 1H), 9.16 (d, 1H).

Example 134(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyrrolidin-1-ylmethyl)thiazole-4-carboxamide

(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyrrolidin-1-ylmethyl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-pyrrolidin-1-ylmethyl-thiazole-4-carboxylic acid (0.244 g, 1.151 mmol)and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2g, 0.767 mmol). The crude product was washed with water. Yield 55.7%.1H-NMR (400 MHz; DMSO-d6): δ 1.23 (d, 3H), 1.72-1.76 (m, 4H), 2.57-2.61(m, 4H), 3.95 (s, 2H), 4.32 (dd, 1H), 4.41 (dd, 1H), 4.41-4.50 (m, 1H),6.96 (d, 1H), 7.85 (d, 1H), 7.95 (dd, 1H), 7.98 (dd, 1H), 8.09 (dd, 1H),8.13 (s, 1H), 8.44 (d, 1H).

Example 135(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxylic acid (0.254 g, 1.215mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(0.4 g, 1.457 mmol). The product was triturated using diethyl ether.Yield 76%. 1H-NMR (400 MHz; DMSO-d6): δ 1.17 (d, 3H), 3.90 (s, 3H), 4.35(dd, 1H), 4.42 (dd, 1H), 4.50 (m, 1H), 6.96 (d, 1H), 7.85 (d, 1H), 7.86(d, 1H), 7.93 (d, 1H), 7.93 (dd, 1H), 8.05 (d, 1H), 8.07 (s, 1H), 8.34(d, 1H), 8.34 (s, 1H).

Example 136(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-imidazole-2-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-imidazole-2-carboxamidewas prepared using the method of Example 34(d) starting from1H-imidazole-2-carboxylic acid (0.206 g, 1.841 mmol) and(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g,1.534 mmol). The crude product was washed with 0.1M HCl, 1M NaCO₃, waterand brine. Yield 76%. 1H-NMR (400 MHz; DMSO): δ 1.23 (d, 3H), 4.31 (dd,1H), 4.38 (dd, 1H), 4.41-4.50 (m, 1H), 6.94 (d, 1H), 7.07 (s, 1H), 7.24(dd, 1H), 7.84 (d, 1H), 7.96 (dd, 1H), 7.99 (dd, 1H), 8.17 (dd, 1H),8.65 (d, 1H), 12.95 (s, 1H).

Example 137(R)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

(R)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-acetylthiazole-4-carboxylic acid (0.597 g, 3.07 mmol) and(R)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.8 g,3.07 mmol). The product was triturated using diethyl ether, isopropanoland DCM, respectively. Yield 24.22%. 1H-NMR (400 MHz; DMSO-d6): δ 1.19(d, 3H), 2.30 (s, 3H), 4.37 (dd, 1H), 4.44 (dd, 1H), 4.47-4.56 (m, 1H),6.96 (d, 1H), 7.87 (d, 1H), 7.92 (dd, 1H), 7.97 (d, 1H), 7.04 (d, 1H),8.49 (d, 1H), 8.61 (s, 1H).

Example 138 (R)-ethyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylate

(R)-ethyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylatewas prepared using the method of Example 34(d) starting from2,4-thiazoledicarboxylic acid, 2-ethyl ester (0.528 g, 2.62 mmol) and(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.6 g,2.186 mmol). The product triturated diethyl ether. Yield 66.3%. 1H-NMR(400 MHz; DMSO-d6): δ 1.17 (d, 3H), 1.34 (t, 3H), 4.34 (dd, 1H),4.39-4.47 (m, 3H), 4.47-4.56 (m, 1H), 6.94 (d, 1H), 7.83 (d, 1H),7.95-7.96 (m, 2H), 8.02 (dd, 1H), 8.55 (s, 1H), 8.61 (d, 1H).

Example 139N—((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide

Sodium borohydride (29.3 mg, 0.773 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C.(R)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide(160 mg, 0.387 mmol) was added and the reaction mixture was warmedslowly to RT while stirring overnight. The crude product was cooled to0° C., the pH was adjusted to 6 and the mixture was evaporated. DCM anda few drops of methanol were added and the crude product was washed with1M Na₂CO₃ and with water. The product was triturated using diethyl etherand DCM and heptane. Yield 33.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.09-1.17(m, 3H), 1.45 (t, 3H), 2.38-4.53 (m, 3H), 4.92-5.02 (m, 1H), 6.23 (dd,1H), 6.96 (dd, 1H), 7.85 (dd, 1H), 7.92-7.97 (m, 2H), 8.07-8.09 (m, 1H),8.10 (d, 1H), 8.33-8.39 (m, 1H).

Example 140(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from4-oxazolecarboxylic acid (0.212 g, 1.841 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g,1.534 mmol). The product was triturated using diethyl ether. Yield32.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11 (d, 3H), 4.31 (dd, 1H), 4.38(dd, 1H), 4.41-4.49 (m, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.97-8.01 (m,2H), 8.15 (dd, 1H), 8.52 (d, 1H), 8.52 (d, 1H), 8.59 (d, 1H).

Example 141(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide

(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from4-oxazolecarboxylic acid (0.202 g, 1.749 mmol) and(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g,1.457 mmol). The product was triturated using diethyl ether. Yield45.5%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11 (d, 3H), 4.31 (dd, 1H), 4.38(dd, 1H), 4.41-4.48 (m, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.96-8.01 (m,2H), 8.15 (dd, 1H), 8.50 (d, 1H), 8.54 (d, 1H), 8.58 (d, 1H).

Example 142(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,5-dimethyloxazole-4-carboxamide

(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,5-dimethyloxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2,5-dimethyl-1,3-oxazole-4-carboxylic acid (0.254 g, 1.749 mmol) and(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g,1.457 mmol). The product was triturated using diethyl ether. Yield54.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.08 (d, 3H), 2.43 (d, 6H), 4.28(dd, 1H), 4.34-4.45 (m, 2H), 6.96 (d, 1H), 7.83 (d, 1H), 7.96-8.01 (m,2H), 8.10 (dd, 1H), 8.23 (d, 1H).

Example 143(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,5-dimethyloxazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,5-dimethyloxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2,5-dimethyl-1,3-oxazole-4-carboxylic acid (0.262 g, 1.804 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g,1.504 mmol). The product was triturated using diethyl ether. Yield64.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.08 (d, 3H), 2.43 (d, 6H), 4.23(dd, 1H), 4.34-4.45 (m, 2H), 6.96 (d, 1H), 7.83 (d, 1H), 7.96-8.01 (m,2H), 8.10 (dd, 1H), 8.23 (d, 1H).

Example 144(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(hydroxymethyl)thiazole-4-carboxamide

Sodium borohydride (108 mg, 2.85 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C.(R)-ethyl-4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate(632.8 mg, 1.426 mmol) was added and the reaction mixture was warmedslowly to RT while stirring overnight. The crude product was cooled to0° C., the pH was adjusted to 6 and the mixture was evaporated. DCM anda few drops of ethanol were added and the crude product was washed with1M Na₂CO₃ and with water. The final product was triturated using diethylether and DCM with some heptane added dropwise. Yield 46.6%. 1H-NMR (400MHz; DMSO-d6): δ 1.12 (d, 3H), 4.31 (dd, 1H), 4.40 (dd, 1H), 4.43-4.51(m, 1H), 4.78 (s, 2H), 6.20 (s, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.95(dd, 1H), 7.98 (dd, 1H), 8.08 (dd, 1H), 8.13 (s, 1H), 8.50 (d, 1H).

Example 145(S)-5-acetyl-N-(1-(3-(4-cyano-3-methoxyphenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamidea) (S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile

(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile wasprepared using the method of Example 34(c) starting from2-nitro-4-(1H-pyrazol-5-yl)benzonitrile (2.0 g, 9.34 mmol) and(S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.6 g, 9.13 mmol). Yield71.0%. H-NMR (400 MHz; DMSO-d6): 0.98 (d, 3H), 3.23-3.33 (m, 1H),4.01-4.12 (m, 2H), 7.08 (d, 1H), 7.90 (d, 1H), 8.19 (d, 1H), 8.34 (dd,1H), 8.69 (d, 1H).

b)(S)-5-acetyl-N-(1-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide

(S)-5-acetyl-N-(1-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (500 mg,1.843 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (341 mg, 2.212mmol). The product was triturated twice using diethyl ether. Yield42.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11-1.27 (m, 3H), 2.48 (s, 3H),4.21-4.57 (m, 3H), 7.03 (d, 1H), 7.29 (s, 1H), 7.86 (d, 1H), 8.09-8.72(m, 4H), 14.1 (bs, 1H).

c)(S)-5-acetyl-N-(1-(3-(4-cyano-3-methoxyphenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide

(S)-5-acetyl-N-(1-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide(0.27 g, 0.663 mmol) was added to a flask and flushed with nitrogen. DryTHF was added and tetrabutylammonium methoxide solution in methanol(1.219 ml, 0.729 mmol) was added dropwise through a septum. During thereaction 1.754 ml of tetrabutylammonium methoxide solution in methanolwas added and after reacting for 6 days the reaction was stopped. Thecrude product was evaporated and dissolved in DCM. The mixture waswashed with water, dried and evaporated. Evaporation residue wasdissolved in 20% methanol/DCM-solvent and filtered through silica wettedwith the same solvent. The product was triturated using a small amountof DCM. Yield 5.00%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H), 2.5 (s,3H), 3.94 (s, 3H), 4.31 (s, 2H), 4.40-4.50 (m, 1H), 6.88 (d, 1H), 7.31(s, 1H), 7.46-7.54 (m, 2H), 7.71 (d, 1H), 7.80 (d, 1H), 8.49 (s, 1H),14.12 (s, 1H).

Example 146 (R)-methyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazol-2-ylcarbamatea) 2-(Methoxycarbonylamino)thiazole-4-carboxylic Acid

Methyl 2-aminothiazole-4-carboxylate (1.0 g, 6.32 mmol) was dissolved indry pyridine and methyl chloroformate (0.733 ml, 9.48 mmol) was addedslowly in RT. The reaction mixture was stirred at RT overnight andevaporated to dryness. The evaporation residue was dissolved in dryTHF/methanol (9:1) mixture, 1M lithium hydroxide (3.50 ml, 3.50 mmol)was added and the reaction mixture was stirred for 4 h in RT. 1M lithiumhydroxide (2.33 ml, 2.33 mmol) was added and the mixture was stirredovernight and evaporated to dryness. DCM was added and pH was adjustedto 3. The product was filtered and dried in vacuum. Yield 76%. 1H-NMR(400 MHz; DMSO-d6): δ 3.75 (s, 3H), 7.95 (s, 1H), 12.05 (s, 1H), 12.76(bs, 1H).

b) (R)-methyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazol-2-ylcarbamate

(R)-methyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazol-2-ylcarbamatewas prepared using the method of Example 34(d) starting from2-(methoxycarbonylamino)thiazole-4-carboxylic acid (0.36 g, 1.460 mmol)and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(0.334 g, 1.217 mmol). The product was triturated using diethyl etherand DCM, respectively. Yield 27.2%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13(d, 3H), 3.77 (s, 3H), 4.33 (d, 1H), 4.34 (d, 1H), 4.37-4.45 (m, 1H),6.96 (d, 1H), 7.72 (s, 1H), 7.83 (d, 1H), 7.87 (d, 1H), 7.93-7.94 (m,2H), 8.04 (t, 1H), 11.85 (s, 1H).

Example 147(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from4-oxazolecarboxylic acid (0.181 g, 1.596 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.430 g, 1.330 mmol). The product was purified by Flash-chromatography.Yield 0.813%. 1H-NMR (400 MHz; CDCl₃): δ 1.27 (d, 3H), 2.57 (s, 3H),4.31 (dd, 1H), 4.43 (dd, 1H), 4.54-4.63 (m, 1H), 6.44 (d, 1H), 7.50 (d,1H), 7.51-7.55 (m, 2H), 7.60 (dd, 1H), 7.85 (d, 1H), 8.22 (d, 1H).

Example 148 (S)-ethyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylate

(S)-ethyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylatewas prepared using the method of Example 34(d) starting from2,4-thiazoledicarboxylic acid, 2-ethyl ester (0.556 g, 2.76 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.6 g,2.301 mmol). The product was triturated using diethyl ether. Yield51.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.18 (d, 3H), 1.34 (t, 3H), 4.34(dd, 1H), 4.39-4.46 (m, 3H), 4.47-4.55 (m, 1H), 6.94 (d, 1H), 7.83 (d,1H), 7.94-7.96 (m, 2H), 8.02 (t, 1H), 8.55 (s, 1H), 8.60 (d, 1H).

Example 149(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(morpholinomethyl)thiazole-4-carboxamidea) Ethyl 2-(morpholinomethyl)thiazole-4-carboxylate

2-Chloromethyl-thiazole-4-carboxylic acid ethyl ester (500 mg, 2.431mmol) and potassium carbonate (504 mg, 3.65 mmol) were dissolved in dryDMF and morpholine (0.212 ml, 2.431 mmol) was added. The reactionmixture was stirred at RT overnight, diluted with DCM and washed withNaHCO₃ and water. Organic phase was evaporated to dryness to yield thetitle compound (93%). 1H-NMR (400 MHz; DMSO-d6): δ 1.30 (t, 3H),2.49-2.54 (m, 4H, overlap with DMSO), 3.58-3.63 (m, 4H), 3.84 (s, 2H),4.29 (q, 2H), 8.47 (s, 1H). m/z [256.3+1].

b) 2-(Morpholinomethyl)thiazole-4-carboxylic Acid Hydrochloride

Ethyl 2-(morpholinomethyl)thiazole-4-carboxylate (578 mg, 2.255 mmol)was dissolved in THF/methanol (9:1) mixture and 1M lithium hydroxide(4.51 ml, 4.51 mmol) was added slowly. The reaction mixture was stirredat RT for 1.5 h, pH was adjusted to 2 and the mixture was evaporated todryness. The evaporation residue was triturated using ethanol. Theprecipitate was filtered and dried in vacuum. The filtrate was alsoevaporated to dryness to give a crude product. m/z [228+1].

c)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(morpholinomethyl)thiazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(morpholinomethyl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-(morpholinomethyl)thiazole-4-carboxylic acid hydrochloride (260 mg,0.982 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (218 mg,0.818 mmol). The product was purified by washing the organic phase with1M HCl, 1M Na₂CO₃, brine and water. Yield 68.7%. 1H-NMR (400 MHz;DMSO-d6): δ 1.23 (d, 3H), 2.50 (t, 4H; overlap with DMSO), 3.61 (t, 4H),3.85 (d, 2H), 4.32 (dd, 1H), 4.40 (dd, 1H), 4.43-4.50 (m, 1H), 6.96 (d,1H), 7.84 (d, 1H), 7.95 (dd, 1H), 7.98 (dd, 1H), 8.02 (dd, 1H), 8.16 (s,1H), 8.46 (d, 1H). m/z [471.0+1].

Example 150(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-methoxyethylamino)thiazole-4-carboxamidea)(R)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

(R)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg,0.384 mmol) and 2-bromo-1,3-thiazole-4-carboxylic acid (96 mg, 0.460mmol). The product was triturated using diethyl ether. Yield 55.8%.1H-NMR (400 MHz; CDCl₃): δ 1.12 (d, 3H), 4.27-4.52 (m, 3H), 6.97 (d,1H), 7.85 (d, 1H), 8.00 (s, 2H), 8.07 (s, 1H), 8.23 (s, 1H), 8.64 (d,1H).

b)(R)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

(R)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide(71 mg, 0.158 mmol) was added into a microwave vial with dry pyridine asa solvent. The mixture was bubbled with nitrogen. 2-methoxyethylamine(0.021 ml, 0.236 mmol) was added and the mixture was heated withmicrowaves at 120° C. During the next few days a total of 0.133 ml of2-methoxyethylamine was added and the reaction mixture was heated for3-12 h at a time. The product was purified by Flash-chromatography.Yield 29.0%. 1H-NMR (400 MHz; CDCl₃): δ 1.23 (d, 3H), 3.40-3.46 (m, 5H),3.58 (t, 2H), 4.29 (dd, 1H), 4.40 (dd, 1H), 4.50-4.57 (m, 1H), 5.38 (t,1H), 6.62 (d, 1H), 7.32 (d, 1H), 7.49 (d, 1H), 7.68 (d, 1H), 7.69 (d,1H), 7.83 (dd, 1H), 7.98 (d, 1H).

Example 151N—((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxamidea) Methyl 2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxylate

Methyl 2-aminothiazole-4-carboxylate (1.0, 6.32 mmol),3-hydroxy-2-butanone (1.045 ml, 12.01 mmol) and acetic acid (2.278 g,37.9 mmol) were dissolved in 1,2-dichloroethane. Sodium triacetoxyborohydride (3.75 g, 17.70 mmol) was added and the reaction mixture wasstirred overnight. Sodium triacetoxy borohydride (3.1 g) was added intwo portions and the reaction mixture was stirred over two nights. 1MNaHCO3 was added slowly and mixture was extracted twice with DCM. DCMphase was dried and evaporated to afford 68.1% of the title product. m/z[230.3+1].

b) 2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxylic Acid

Methyl 2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxylate (1.092 g, 4.75mmol) was dissolved in THF/water (9:1) mixture and 1M lithium hydroxide(9.49 ml, 9.49 mmol) was added slowly. The reaction mixture was stirredat RT for 1 h and evaporated to dryness. DCM and water was added and pHwas adjusted to 2. Acidic water phase was washed twice with DCM andevaporated to dryness. Evaporation residue was dissolved in ethanol, aprecipitation was filtered and the filtrate was evaporated to dryness togive a crude product. m/z [216.3+1].

c)N—((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxamide

N—((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxylic acid (1.35 g, 6.24mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(1.356 g, 5.20 mmol). The product was purified by Flash-chromatography.Yield 14.45%. 1H-NMR (400 MHz; DMSO-d6): δ 0.98-1.19 (m, 9H), 3.57-3.72(m, 2H), 4.23-4.47 (m, 3H), 4.67 (d, 1H), 6.94-6.97 (m, 1H), 7.11-7.14(m, 1H), 7.37-7.53 (m, 1H), 7.69-7.80 (m, 1H), 7.80-7.85 (m, 1H),7.90-8.00 (m, 2H), 8.06-8.09 (m, 1H).

Example 152(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(hydroxymethyl)thiazole-4-carboxamidea) (S)-ethyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylate

(S)-ethyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylatewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (600 mg,2.301 mmol) and 2,4-thiazoledicarboxylic acid, 2-ethyl ester (556 mg,2.76 mmol). The product was triturated using diethyl ether. Yield 51.9%.1H-NMR (400 MHz; DMSO-d6): δ 1.18 (d, 3H), 1.34 (t, 3H), 4.29-4.58 (m,5H), 6.97 (d, 1H), 7.83 (d, 1H), 7.94-7.96 (m, 2H), 8.02 (t, 1H), 8.55(s, 1H), 8.60 (d, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(hydroxymethyl)thiazole-4-carboxamide

Sodium borohydride (86 mg, 2.262 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C. (S)-ethyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate(502 mg, 1.131 mmol) was added and the reaction mixture was warmedslowly to RT while stirring overnight. The crude product was cooled to0° C., water was added dropwise, the pH was adjusted to 7 and themixture was evaporated. DCM and a few drops of methanol were added andthe crude product was washed with 1M Na₂CO₃ and with water. Yield 58.6%.1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 4.31 (dd, 1H), 4.40 (dd, 1H),4.43-4.51 (m, 1H), 4.79 (d, 2H), 6.20 (t, 1H), 6.95 (d, 1H), 7.84 (d,1H), 7.96 (dd, 1H), 7.98 (dd, 1H), 8.08 (dd, 1H), 8.13 (s, 1H), 8.50 (d,1H).

Example 153(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-bromo-1,3-thiazole-4-carboxylic acid (0.6 g, 2.88 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.627 g,2.403 mmol). The product was triturated using diethyl ether. Yield65.5%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 4.23 (dd, 1H), 4.39(dd, 1H), 4.42-4.50 (m, 1H), 6.96 (d, 1H), 7.84 (d, 1H), 8.00-8.01 (m,2H), 8.07 (dd, 1H), 8.23 (s, 1H), 8.64 (d, 1H).

Example 154(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamide

(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methyl-amino)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-(methylamino)thiazole-4-carboxylic acid (0.34 g, 2.149 mmol) and(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.467 g,1.791 mmol). The product was purified by Flash-chromatography. Yield9.08%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 2.85 (d, 3H),4.30-4.42 (m, 3H), 6.96 (d, 1H), 7.18 (d, 1H), 7.59 (d, 1H), 7.84 (d,1H), 7.91 (d, 1H), 7.95-7.96 (m, 2H), 8.08 (dd, 1H).

Example 155(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide

(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-amino-1,3-oxazole-4-carboxylic acid (0.196 g, 1.527 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.437 g, 1.272 mmol). The product was purified by Flash-chromatography.Yield 29.0%. 1H-NMR (400 MHz; CDCl₃): δ 1.23 (d, 3H), 2.58 (s, 3H), 4.29(dd, 1H), 4.39 (dd, 1H), 4.54 (m, 1H), 4.59 (s, 2H), 6.44 (d, 1H), 7.31(d, 1H), 7.50 (d, 1H), 7.53 (dd, 1H), 7.58 (dd, 1H), 7.68 (s, 1H).

Example 156(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-Aminothiazole-4-carboxylic acid (0.504 g 3.49 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.8 g, 2.91 mmol). The product was purified by Flash-chromatography.Yield 16.65%. 1H-NMR (400 MHz; CDCl₃): δ 1.24 (d, 3H), 2.58 (s, 3H),4.30 (dd, 1H), 4.40 (dd, 1H), 4.53 (m, 1H), 4.86 (s, 2H), 7.44 (d, 1H),7.35 (s, 1H), 7.51 (d, 1H), 7.54 (dd, 1H), 7.57 (d, 1H), 7.63 (d, 1H).

Example 157(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)thiazole-4-carboxamide

(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(piperidin-4-yl)thiazole-4-carboxamide(80 mg, 0.176 mmol) was added into a flask under nitrogen atmosphere.Dry pyridine was added along with methanesulfonyl chloride (20.14 mg,0.176 mmol) and the mixture was stirred overnight. The reaction wasstopped by adding water. The reaction mixture was diluted with DCM andwashed with 1M Na₂CO₃ and water. The product was triturated usingdiethyl ether. Yield 35.5%. 1H-NMR (400 MHz; CDCl₃): δ 1.29 (d, 3H),1.92 (m, 2H), 2.18 (m, 2H), 2.81 (dd, 1H), 2.84 (s, 3H), 3.08 (m, 1H),3.89 (m, 2H), 4.34 (dd, 1H), 4.42 (dd, 1H), 4.59 (m, 1H), 6.63 (d, 1H),7.50 (d, 1H), 7.67 (d, 1H), 7.68 (d, 1H), 7.77 (dd, 1H), 7.98 (d, 1H),8.01 (s, 1H).

Example 158(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-methoxyethylamino)thiazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide(0.2 g, 0.444 mmol) and dry pyridine were added into a microwave vialunder nitrogen atmosphere. 2-methoxyethylamine (0.193 ml, 2.219 mmol)was added and the mixture was heated with microwaves at 120° C. for 10h. Afterwards a total of 0.232 ml of 2-methoxyethylamine was added andthe mixture was heated for another 10 h. The product was purified byFlash-chromatography. Yield 47.8%. 1H-NMR (400 MHz; CDCl₃): δ 1.22 (d,3H), 3.41 (s, 3H), 3.44 (m, 2H), 3.57 (m, 2H), 4.29 (dd, 1H), 4.40 (dd,1H), 4.54 (m, 1H), 5.39 (t, 1H), 6.62 (d, 1H), 7.33 (d, 1H), 7.49 (d,1H), 7.68 (dd, 1H), 7.69 (d, 1H), 7.83 (dd, 1H), 7.98 (dd, 1H).

Example 159(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(pyridin-4-yl)-1H-pyrazole-3-carboxamide

The title compound was prepared as described in Example 34(d), startingfrom 1-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid (47.5 mg, 0.251mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(70 mg, 0.251 mmol). The precipitate that formed during the reaction wasfiltered out of the reaction mixture was washed with 2×5 ml of water anddried with vacuum at 40° C. Yield 73.7%. 1H-NMR (400 MHz; DMSO-d6): δ1.18 (d, 3H), 4.31-4.42 (m, 2H), 4.43-4.54 (m, 1H), 6.90 (d, 1H), 7.01(dd, 1H), 7.79-8.01 (m, 5H), 8.39 (d, 1H), 8.66-8.73 (m, 2H), 8.77 (d,1H).

Example 160(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-bromo-1,3-thiazole-4-carboxylic acid (0.909 g, 4.37 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(1 g, 3.64 mmol). The product was purified by Flash-chromatography.Yield 45.0%. 1H-NMR (400 MHz; CDCl₃): δ 1.25 (d, 3H), 2.61 (s, 3H), 4.29(dd, 1H), 4.45 (dd, 1H), 4.60 (m, 1H), 6.46 (d, 1H), 7.51 (d, 1H), 7.57(dd, 1H), 7.61 (dd, 1H), 7.98 (d, 1H), 8.04 (s, 1H).

Example 161(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-((dimethylamino)methyl)thiazole-4-carboxamidea) Ethyl 2-((dimethylamino)methyl)thiazole-4-carboxylate

2-Chloromethyl-thiazole-4-carboxylic acid ethyl ester (500 mg, 2.431mmol) and potassium carbonate (504 mg, 3.65 mmol) were dissolved in dryDMF. Dimethylamine hydrochloride (218 mg, 2.67 mmol) in dry DMF wasadded slowly to the reaction mixture and stirred at RT over threenights. DCM was added and the mixture was washed with concentratedNaHCO₃ and water. Organic phase was evaporated to dryness and theproduct was purified by Flash-chromatography. Yield 34.2%. 1H-NMR (400MHz; CDCl₃): δ 1.41 (t, 3H), 2.49 (s, 6H), 3.99 (s, 2H) 4.43 (q, 2H),8.20 (s, 1H).

b) 2-((Dimethylamino)methyl)thiazole-4-carboxylic Acid

Ethyl 2-((dimethylamino)methyl)thiazole-4-carboxylate (147 mg, 0.686mmol) was dissolved in THF/methanol mixture (9:1) and 1M lithiumhydroxide (1.372 ml, 1.372 mmol) was added slowly. The reaction mixturewas stirred at RT for 3 h, pH was adjusted to 2 and the mixture wasevaporated to dryness to yield the title compound as a crude product.m/z [186.2+1].

c)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-((dimethylamino)methyl)thiazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-((dimethylamino)methyl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.149 g,0.573 mmol) and 2-((dimethylamino)methyl)thiazole-4-carboxylic acid (128mg, 0.687 mmol). The product was purified by Flash-chromatography. Yield0.814%. 1H-NMR (400 MHz; CDCl₃): δ 1.26 (d, 3H), 2.37 (s, 6H), 3.76 (d,2H), 4.32 (dd, 1H), 4.42 (dd, 1H), 4.59 (m, 1H), 6.62 (d, 1H), 7.50 (d,1H), 7.67 (dd, 1H), 7.81 (dd, 1H), 7.90 (d, 1H), 7.99 (dd, 1H), 8.06 (s.1H).

Example 162(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxamidea) Ethyl 2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxylate

Ethyl 2-(4-piperidino)-1,3-oxazole-4-carboxylate (500 mg, 2.230 mmol)and triethylamine (0.466 ml, 3.34 mmol) were dissolved in dry DCM andcooled down to 0° C. Methanesulfonyl chloride (0.190 ml, 2.453 mmol) wasadded slowly at 0° C. and the reaction mixture was stirred at RTovernight. Small amount of water was added carefully and organic phasewas washed with 1M Na₂CO₃ and water. Organic phase was dried andevaporated to yield the title compound 89%. 1H-NMR (400 MHz; CDCl₃): δ1.38 (t, 3H), 1.97-2.11 (m, 2H), 2.15-2.24 (m, 2H), 2.81 (s, 3H),2.88-3.07 (m, 3H), 3.72-3.82 (m, 2H), 4.39 (q, 2H), 8.17 (s, 1H).

b) 2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxylic Acid

Ethyl 2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxylate (590 mg,1.951 mmol) was dissolved in THF/methanol mixture (9:1) and 1M lithiumhydroxide (3.90 ml, 3.90 mmol) was added slowly. The reaction mixturewas stirred at RT for 1 h, diluted with water and pH was adjusted to1.5. The mixture was extracted three times with ethyl acetate. Ethylacetate phases were combined and evaporated to yield the title compound(74.7%). 1H-NMR (400 MHz; DMSO): δ 1.68-1.81 (m, 2H), 2.06-2.15 (m, 2H),2.85-2.96 (m, 5H), 2.99-3.10 (m, 1H), 3.51-3.59 (m, 2H), 8.67 (s, 1H),13.02 (bs, 1H).

c)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxylic acid (0.4 g,01.458 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.317 g,01.215 mmol). The product was purified by extracting it from DCM with0.1 M HCl, 1 M Na₂CO₃, water and brine. Yield 87%. 1H-NMR (400 MHz;CDCl₃): δ 1.25 (d, 3H), 1.97 (m, 2H), 2.15 (m, 2H), 2.83 (s, 3H), 2.89(m, 3H), 3.81 (m, 2H), 4.30 (dd, 1H), 4.41 (dd, 1H), 4.57 (m, 1H), 6.63(d, 1H), 7.46 (d, 1H), 7.49 (d, 1H), 7.68 (dd, 1H), 7.79 (dd, 1H), 8.01(dd, 1H), 8.11 (s, 1H).

Example 163(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(2-fluoroethyl)-2-methyl-1H-imidazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide(130 mg, 0.269 mmol) was suspended in THF (5 ml). Cesium carbonate (123mg, 0.376 mmol) and 1-iodo-2-fluoroethane (0.066 ml, 0.807 mmol) wereadded and the resulting mixture was stirred overnight at RT. Next day0.2 ml of 1-iodo-2-fluoroethane was added and the mixture was left toreact over the weekend. 1 ml of water was added and the reaction mixturewas evaporated. The product was purified with LC/MS-trigger. Yield27.5%. ¹H-NMR (400 MHz; CDCl₃): δ 1.22 (d, 3H), 2.46 (s, 3H), 4.13-4.24(m, 2H), 4.29 (dd, 1H), 4.40 (dd, 1H), 4.52-4.62 (m, 1H), 4.59-4.74 (m,2H), 6.59 (d, 1H), 7.50-7.54 (m, 2H), 7.69 (d, 1H), 7.73-7.75 (m, 1H),7.78 (bs, 1H).

Example 164(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(hydroxymethyl)thiazole-4-carboxamidea) (S)-ethyl4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate

(S)-ethyl4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylatewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(400 mg, 1.165 mmol) and 2,4-thiazoledicarboxylic acid, 2-ethyl ester234 mg, 1.165 mmol). The product was purified by Flash-chromatography.Yield 16.1%. 1H-NMR (400 MHz; CDCl3): δ 1.31 (d, 3H), 1.44 (t, 3H), 2.55(s, 3H), 4.31-4-46 (m, 2H), 4.50 (q, 2H), 4.56-4.68 (m, 1H), 6.42 (d,1H), 7.50 (d, 1H), 7.54-7.61 (m, 2H), 7.80 (bd, 1H), 8.34 (s, 1H).

c)(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(hydroxymethyl)thiazole-4-carboxamide

Sodium borohydride (14.21 mg, 0.376 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C. (S)-ethyl4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate(86 mg, 0.188 mmol) was added and the reaction mixture was warmed slowlyto RT while stirring overnight. The crude product was cooled to 0° C.,the pH was adjusted to 7 and the mixture was evaporated. DCM and a fewdrops of methanol were added and the crude product was washed with 1MNa₂CO₃ and with water. Yield 89%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d,3H), 2.53 (s, 3H), 4.23 (dd, 1H), 4.40 (dd, 1H), 4.49 (m, 1H), 4.75 (d,2H), 6.21 (t, 1H), 6.62 (d, 1H), 7.64 (dd, 1H), 7.82 (dd, 1H), 7.85 (d,1H), 8.13 (s, 1H), 8.43 (d, 1H).

Example 165(S)—N4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-N2,N2-dimethylthiazole-2,4-dicarboxamide

(S)—N4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-N2,N2-dimethylthiazole-2,4-dicarboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylicacid (0.2 g, 0.428 mmol) and dimethylamine hydrochloride (0.029 g, 0.357mmol). The product was purified by Flash-chromatography. Yield 23.42%.1H-NMR (400 MHz; DMSO-d6): δ 1.18 (d, 3H), 3.05 (s, 3H), 3.45 (s, 3H),4.37 (m, 2H), 4.46 (m, 1H), 6.94 (d, 1H), 7.84 (d, 1H), 7.89 (dd, 1H),7.95 (d, 1H), 8.04 (d, 1H), 8.30 (d, 1H), 8.43 (s, 1H).

Example 166(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(dimethylamino)thiazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide(0.247 g, 0.531 mmol) was added into a microwave test tube with drypyridine. The mixture was bubbled with nitrogen and dimethylamine 2 M inTHF (1.329 ml, 2.66 mmol) was added. The reaction mixture was heatedwith microwaves at 120° C. for 10 h. The crude product was evaporated,diluted with DCM, washed with 1M Na₂CO₃ and and water. The product waspurified with Flash-chromatography. Yield 63.2%. 1H-NMR (400 MHz;CDCl₃): δ 1.25 (d, 3H), 2.53 (s, 3H), 3.00 (s, 6H), 4.32 (dd, 1H), 4.41(dd, 1H), 4.55 (m, 1H), 6.41 (d, 1H), 7.30 (d, 1H), 7.52 (m, 3H), 7.74(d, 1H).

Example 167(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(trifluoromethyl)thiazole-4-carboxamidea) 2-(Trifluoromethyl)thiazole-4-carboxylic Acid

Ethyl 2-(trifluoromethyl)thiazole-4-carboxylate (400 mg, 1.176 mmol) wasdissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (3.55ml, 3.55 mmol) was added slowly. The reaction mixture was stirred at RTfor 1 hour, pH was adjusted to 2 and the reaction mixture was extractedthree times with ethyl acetate. Ethyl acetate phases were combined,dried and evaporated to dryness. Yield 93%. m/z [197.1+1]

b)(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(trifluoromethyl)thiazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(trifluoromethyl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(376 mg, 1.370 mmol) and 2-(trifluoromethyl)thiazole-4-carboxylic acid(324 mg, 1.644 mmol). The product was triturated using DCM and heptane.Yield 13.35%. 1H-NMR (400 MHz; CDCl₃): δ 1.27 (d, 3H), 2.57 (s, 3H),4.31 (dd, 1H), 4.46 (dd, 1H), 4.65 (m, 1H), 4.45 (d, 1H), 7.51 (d, 1H),7.53 (d, 1H), 7.57 (d, 1H), 8.03 (d, 1H), 8.33 (s, 1H).

Example 1681-(4-((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazol-2-yl)ethylAcetate

N—((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide(0.1 g, 0.233 mmol) and DMAP (2.87 mg, 0.023 mmol) were added into aflask under nitrogen atmosphere. Pyridine was added, the mixture cooledto 0° C. and acetic anhydride (0.023 ml, 0.244 mmol) was added dropwise.The mixture was slowly heated to RT and stirred. After 2.5 h the mixturewas evaporated. The product was purified with Flash-chromatography.Yield 80%. 1H-NMR (400 MHz; CDCl₃): δ 1.27 (d, 3H), 1.59 (dd, 3H), 2.15(d, 3H), 2.56 (d, 3H), 4.33 (dd, 1H), 4.43 (dd, 1H), 4.60 (m, 1H),6.03-6.11 (m, 1H), 6.43 (d, 1H), 7.50-7.58 (m, 3H), 7.77-7.88 (m, 1H),8.05 (s, 1H).

Example 169(S)-2-((1H-imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamidea) 2-(Chloromethyl)oxazole-4-carboxylic Acid

Methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate (1.0 g, 5.70 mmol) wasdissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (11.39ml, 11.39 mmol) was added slowly. The reaction mixture was stirred at RTfor 1 h, diluted with water and pH was adjusted to 2. The reactionmixture was extracted three times with ethyl acetate. Ethyl acetatephases were combined, dried and evaporated to dryness to yield the titlecompound (94%). 1H-NMR (400 MHz; DMSO₃): δ 4.93 (s, 2H), 8.80 (s, 1H),13.20 (bs, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(chloromethyl)oxazole-4-carboxamide

2-(chloromethyl)oxazole-4-carboxylic acid (400 mg, 2.476 mmol) and1,3-DCC (5110 mg, 2.476 mmol) were dissolved in dry DCM and stirred for30 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(646 mg, 2.476 mmol) in dry DCM was added to the reaction mixture andstirred at RT overnight. The reaction mixture was diluted with DCM andwashed twice with water. Organic phase was evaporated to dryness and theproduct was purified with Flash-chromatography. Yield 36.9%. m/z[404.3+1].

c)S)-2-((1H-imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide

Sodium hydride (11.87 mg, 0.297 mmol) was added into a flask undernitrogen atmosphere. The flask was cooled to 0° C. and DMF was addedthrough a septum. Imidazole (13.47 mg, 0.198 mmol) was added and themixture was stirred for 60 min in RT. The mixture was again cooled to 0°C. and(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(chloromethyl)oxazole-4-carboxamide(80 mg, 0.198 mmol) in DMF was added dropwise. The reaction mixture wasstirred overnight in RT. DMF was evaporated and the resulting crudeproduct was dissolved in DCM, washed with brine and evaporated. Theproduct was triturated using diethyl ether and purified byFlash-chromatography. Yield 8.23%. 1H-NMR (400 MHz; CDCl₃): δ 1.24 (d,3H), 4.29 (dd, 1H), 4.41 (dd, 1H), 4.58 (m, 1H), 5.26 (s, 2H), 6.64 (d,1H), 7.00 (t, 1H), 7.11 (t, 1H), 7.49 (d, 1H), 7.60 (s, 1H), 7.61 (d,1H), 7.68 (d, 1H), 7.78 (dd, 1H), 8.08 (d, 1H), 8.17 (s, 1H).

Example 170(S)—N4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-N2,N2-dimethylthiazole-2,4-dicarboxamide

(S)—N4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-N2,N2-dimethylthiazole-2,4-dicarboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylicacid (0.2 g, 0.340 mmol) and dimethylamine hydrochloride (0.023 g, 0.283mmol). The product was purified by Flash-chromatography and trituratedusing diethyl ether, respectively. Yield 4.18%. 1H-NMR (400 MHz; CDCl₃):δ 1.27 (d, 3H), 2.51 (s, 3H), 3.09 (s, 3H), 3.24 (s, 3H), 4.23 (dd, 1H),4.45 (dd, 1H), 4.62 (m, 1H), 6.41 (d, 1H), 7.48 (d, 1H), 7.51 (d, 1H),7.54 (dd, 1H), 7.85 (d, 1H), 8.27 (s, 1H).

Example 171(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-hydroxypropan-2-yl)thiazole-4-carboxamidea) (S)-ethyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylate

(S)-ethyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylatewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (540 mg,2.071 mmol) and 2,4-thiazoledicarboxylic acid, 2-ethyl ester (500 mg,2.485 mmol). Yield 82%. 1H-NMR (400 MHz; DMSO₃): δ 1.18 (d, 3H), 1.35(t, 3H), 4.35 (dd, 1H), 4.39-4.57 (m, 4H), 6.94 (d, 1H), 7.84 (d, 1H),7.95 (m, 2H), 8.02 (m, 1H), 8.55 (s, 1H), 8.61 (d, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-hydroxypropan-2-yl)thiazole-4-carboxamide

(S)-ethyl4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylate(0.755 g, 1.701 mmol) was dissolved in dry THF under nitrogenatmosphere. The solution was cooled to −78° C. with acetone-dryice-bath. Methylmagnesium bromide, 3 M solution in Et₂O (1.134 ml, 3.40mmol), was added and the reaction mixture was stirred in RT. After thereaction was finished, saturated ammoniumchloride, water and DCM wasadded. The organic phase was washed with water. The product was purifiedwith Flash-chromatography. Yield 4.24%. 1H-NMR (400 MHz; CDCl₃): δ 1.28(d, 3H), 1.65 (d, 6H), 3.00 (s, 1H), 4.35 (dd, 1H), 4.42 (dd, 1H), 4.58(m, 1H), 6.62 (d, 1H), 7.50 (d, 1H), 7.66 (d, 1H), 7.67 (d, 1H), 7.80(dd, 1H), 7.91 (d, 1H), 8.00 (s, 1H).

Example 172(R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)butan-2-yl)-oxazole-4-carboxamide

(R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)butan-2-yl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from4-oxazolecarboxylic acid (0.2 g, 1.769 mmol) and(R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.532 g, 1.474 mmol). The product was triturated using diethyl ether.Yield 29.9%. 1H-NMR (400 MHz; CDCl₃): δ 1.02 (t, 3H), 1.58 (m, 2H), 2.57(s, 3H), 4.39 (m, 3H), 6.43 (d, 1H), 7.45 (d, 1H), 7.49 (d, 1H), 7.53(dd, 1H), 7.58 (d, 1H), 7.85 (d, 1H), 8.22 (d, 1H).

Example 173(S)-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazol-2-yl)methyl2-(dimethylamino)acetate

(S)-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazol-2-yl)methyl2-(dimethylamino)acetate was prepared using the method of Example 34(d)starting from N,N-dimethylglycine (0.062 g, 0.597 mmol) and(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(hydroxymethyl)thiazole-4-carboxamide(0.2 g, 0.498 mmol). The product was triturated using diethyl ether andpurified by Flash-chromatography, respectively. Yield 39.5%. 1H-NMR (400MHz; CDCl₃): δ 1.25 (d, 3H), 2.39 (s, 6H), 3.30 (s, 2H), 4.31 (dd, 1H),4.43 (dd, 1H), 4.60 (m, 1H), 5.43 (d, 2H), 6.63 (d, 1H), 7.49 (d, 1H),7.70 (d, 1H), 7.84 (dd, 1H), 7.95 (d, 1H), 7.97 (d, 1H), 8.12 (s, 1H).

Example 174(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamidea)N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thiazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide(300 mg, 0.666 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronicacid pinacol ester (222 mg, 0.799 mmol),tetrakis(triphenyl-phosphine)palladium (23 mg, 0.020 mmol), THF and 2MNa₂CO₃ solution were added in a microwave flask and heated in microwaveat 120° C. for 2 h. 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronicacid pinacol ester (37 mg) and tetrakis(tri-phenylphosphine)palladium (8mg) were added and the reaction mixture was heated in 120° C. for 1 h.The reaction mixture was diluted with DCM and washed twice with Na₂CO₃solution. Organic phase was dried and evaporated to dryness. The productwas purified by Flash-chromatography. Yield 3.7%. m/z [522.0+1].

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide

N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thiazole-4-carboxamide(13 mg, 0.025 mmol) was added into a flask under nitrogen atmosphere.10% HCl/EtOH (0.028 ml, 0.062 mmol) was added and the reaction mixturewas stirred in RT for 3 h. The reaction mixture was diluted with ethylacetate and washed with 1M Na₂CO₃. The organic phase was dried, filteredand evaporated. Yield 94%. 1H-NMR (400 MHz; MeOD): δ 1.30 (d, 3H), 4.38(dd, 1H), 4.45 (dd, 1H), 4.59 (m, 1H), 6.75 (d, 1H), 6.83 (d, 1H), 7.61(d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.84 (dd, 1H), 7.95 (d, 1H), 8.06(s, 1H).

Example 175(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamidea)(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide

Into a flask containing3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.148g, 0.350 mmol) and anhydrous HOBt (0.047 g; 0.350 mmol), dichloromethane(2 ml), DIPEA (0.122 ml; 0.700 mmol) and EDCI (0.067 g; 0.350 mmol) wereadded and stirred for 10 min at RT.(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.100 g, 0.269 mmol) dissolved in 2 ml of dichloromethane was added andthe resulting mixture stirred overnight. Next day the temperature wasraised to 50° C. and more EDCI (0.067 g; 0.350 mmol) was added. Thereaction mixture was allowed to react with stirring for 4 h. DCM wasadded and the organic layer was extracted with 1M Na₂CO₃ and water. Theorganic layer was then evaporated and the residue purified with flashchromatography. LC-MS: [M+1]=684.133.

b)(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide

Into a flask containing(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide(0.073 g, 0.107 mmol), a mixture containing THF (9 ml), formic acid(2.459 ml, 53.4 mmol) and water (0.1 ml) was added. The resultingmixture was stirred at RT for 24 h. The solvents were evaporated.Acetonitrile (15 ml) was added and evaporated. This was repeated 3 moretimes. The product was purified with LC/MS-trigger. Yield 46.3%. ¹H-NMR(400 MHz; DMSO-d6): δ 1.21 (d, 3H), 4.32-4.40 (m, 2H), 4.42-4.54 (m,1H), 7.02 (d, 1H), 7.81-7.92 (m, 4H), 7.94 (s, 1H), 9.43 (d, 1H), 12.69(s, 1H).

Example 176N—((R)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)butan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamidea)(R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile

(R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrilewas prepared using the method of Example 99 starting from2-chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile (2.0 g, 9.19 mmol) and(R)-tert-butyl 1-hydroxybutan-2-ylcarbamate (3.48 g, 18.38 mmol). Yield56.5%. m/z [288.8+1].

b)(R)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)butan-2-yl)thiazole-4-carboxamide

(R)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)butan-2-yl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(489 mg, 1.355 mmol) and 2-acetylthiazole-4-carboxylic acid (278 mg,1.626 mmol). The product was purified by Flash-chromatography. Yield11.4%. 1H-NMR (400 MHz; CDCl₃): δ 1.05 (t, 3H), 1.56-1.67 (m, 2H), 2.53(s, 3H), 2.53 (s, 3H), 4.36-4.52 (m, 3H), 6.42 (d, 1H), 7.47-7.55 (m,3H), 7.88 (d, 1H), 8.39 (s, 1H).

c)N—((R)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)butan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide

Sodium borohydride (7.19 mg, 0.190 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C.(R)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)butan-2-yl)thiazole-4-carboxamide(42 mg, 0.095 mmol) was added and the reaction mixture was warmed slowlyto RT while stirring overnight. The crude product was cooled to 0° C.,the pH was adjusted to about 3 and the mixture was evaporated. 5%DCM/MeOH was added and the crude product was washed with 1M NaHCO₃,water and dried. Yield 74.2%. 1H-NMR (400 MHz; CDCl₃): δ 1.03 (m, 3H),1.56-1.59 (m, 3H), 2.54 & 2.55 (2× broad s, 3H), 4.34-4.46 (m, 3H), 5.07(dd, 1H), 6.41-6.43 (m, 1H), 7.46-7.54 (m, 3H), 7.80-7.89 (m, 1H), 8.02(s, 1H).

Example 177N—((S)-2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-5-(1-hydroxyethyl)isoxazole-3-carboxamidea) 5-Acetylisoxazole-3-carboxylic Acid

Ethyl 5-acetylisoxazole-3-carboxylate (300 mg, 1.638 mmol) was dissolvedin THF/methanol mixture (9:1) and 1M lithium hydroxide (3.28 ml, 3.28mmol) was added slowly. The reaction mixture was stirred at RT for 40min, diluted with water and pH was adjusted to 3. The reaction mixturewas extracted three times with ethyl acetate. Ethyl acetate phases werecombined, washed with brine, dried and evaporated to dryness to yieldthe title compound (29.9%). m/z [155.1+1].

b)(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-isoxazole-3-carboxamide

(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (106mg, 0.408 mmol) and 5-acetylisoxazole-3-carboxylic acid (76 mg, 0.490mmol). The product was purified by Flash-chromatography. Yield 24.6%.1H-NMR (400 MHz; CDCl₃): δ 1.63 (d, 3H), 2.63 (s, 3H), 3.78-3.88 (m,1H), 3.91-4.00 (m, 1H), 4.59-4.69 (m, 1H), 6.63 (d, 1H), 7.29 (s, 1H),7.50 (s, 1H), 7.67-7.77 (m, 2H), 7.82 (dd, 1H), 8.05 (d, 1H).

c)N—((S)-2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-5-(1-hydroxyethyl)isoxazole-3-carboxamide

Sodium borohydride (6.41 mg, 0.169 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C.(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)isoxazole-3-carboxamide(33.7 mg, 0.085 mmol) was added and the reaction mixture was warmedslowly to RT while stirring overnight. The crude product was cooled to0° C., the pH was adjusted to about 3 and the mixture was evaporated. 5%of DCM/MeOH was added and the crude product was washed with 1M NaHCO₃,water and dried. Yield 96%. 1H-NMR (400 MHz; CDCl₃): δ 1.57-1.65 (m, 3H)3.75-3.84 (m, 1H), 3.87-3.95 (m, 1H), 4.57-4.67 (m, 1H), 5.03 (q, 1H),6.61 (d, 1H), 6.62 (s, 1H), 7.50 (d, 1H), 7.56-7.63 (m, 1H), 7.65-7.69(2×s, 1H), 7.81 (dd, 1H), 8.01 (d, 1H).

Example 178(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide

(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-acetyloxazole-4-carboxylic acid (372 mg, 2.400 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(549 mg, 2.000 mmol). The product was triturated using diethyl ether andpurified by Flash-chromatography, respectively. Yield 12.47%. 1H-NMR(400 MHz; CDCl₃): δ 1.27 (d, 3H), 2.59 (s, 3H), 2.60 (s, 3H), 4.31 (dd,1H), 4.45 (dd, 1H), 4.64 (m, 1H), 6.45 (d, 1H), 7.51 (d, 1H), 7.56 (m,2H), 7.68 (d, 1H), 8.31 (s, 1H).

Example 179(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)picolinamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)picolinamidewas prepared using the method of Example 34(d) starting from picolinicacid (0.227 g, 1.841 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g,1.534 mmol). Yield 73.7%. 1H-NMR (400 MHz; CDCl₃): δ 1.26 (d, 3H), 4.31(dd, 1H), 4.45 (dd, 1H), 4.62 (m, 1H), 6.63 (d, 1H), 7.46 (m, 1H), 7.50(d, 1H), 7.67 (d, 1H), 7.81 (dd, 1H), 7.86 (m, 1H), 8.09 (d, 1H), 8.19(m, 1H), 8.65 (m, 1H), 8.86 (d, 1H).

Example 180N—((S)-2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-2-(1-hydroxyethyl)oxazole-4-carboxamidea)(S)-2-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propyl)oxazole-4-carboxamide

(S)-2-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (521mg, 2.00 mmol) and 2-acetyloxazole-4-carboxylic acid (372 mg, 2.40mmol). The product was purified by Flash-chromatography. Yield 36.0%.1H-NMR (400 MHz; CDCl₃): δ 1.62 (d, 3H), 2.61 (s, 3H), 3.75-3.98 (m,2H), 4.59-4.71 (m, 1H), 6.62 (d, 1H), 7.45-7.53 (m, 2H), 7.71 (d, 1H),7.86 (dd, 1H), 7.98 (d, 1H), 8.32 (s, 1H).

b)N—((S)-2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-2-(1-hydroxyethyl)oxazole-4-carboxamide

Sodium borohydride (0.051 g, 1.352 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C.(S)-2-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)oxazole-4-carboxamide(0.269 g, 0.676 mmol) was added and the reaction mixture was warmedslowly to RT while stirring overnight. The crude product was cooled to0° C., the pH was adjusted below 7 and the mixture was evaporated. 5% ofDCM/MeOH was added and the crude product was washed with 1M NaHCO₃,water and dried. Yield 84%. 1H-NMR (400 MHz; CDCl₃): δ 1.58 (d, 3H),1.61 (d, 3H), 2.40 (d, 1H), 3.79 (m, 1H), 3.89 (m, 1H), 4.62 (m, 1H),4.94 (m, 1H), 6.61 (d, 1H), 7.46 (m, 1H), 7.49 (d, 1H), 7.69 (d, 1H),7.85 (dd, 1H), 7.98 (d, 1H), 8.15 (s, 1H).

Example 181N—((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)oxazole-4-carboxamide

Sodium borohydride (0.037 g, 0.971 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C.(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide(0.2 g, 0.486 mmol) was added and the reaction mixture was warmed slowlyto RT while stirring overnight. The crude product was cooled to 0° C.,the pH was adjusted below 7 and the mixture was evaporated. 5% ofDCM/MeOH was added and the crude product was washed with 1M NaHCO₃,water and dried. The product was purified with Flash-chromatography.Yield 55.4%. 1H-NMR (400 MHz; CDCl₃): δ 1.25 (d, 3H), 1.59 (d, 3H), 2.50(s, 1H), 2.58 (s, 3H), 4.30 (dd, 1H), 4.42 (dd, 1H), 4.59 (m, 1H), 4.94(m, 1H), 6.44 (d, 1H), 7.54 (m, 4H), 8.14 (s, 1H).

Example 182(S)-2-(3-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)isoxazol-5-yl)propan-2-ylacetate

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide(97 mg, 0.234 mmol) and DMAP (2.89 mg, 0.023 mmol) were dissolved inpyridine under nitrogen atmosphere. The reaction mixture was cooled to0° C., acetic anhydride (25.1 mg, 0.246 mmol) was added and the reactionmixture stirred for 2 h in RT. The mixture was again cooled to 0° C. and10 μl of acetic anhydride was added. The reaction mixture was stirred inRT overnight after which the solvent was evaporated. Yield 99%. 1H-NMR(400 MHz; CDCl₃): δ 1.22 (d, 3H), 1.80 (s, 6H), 2.05 (s, 3H), 4.25 (dd,1H), 4.42 (dd, 1H), 4.58 (m, 1H), 6.58 (s, 1H), 6.63 (d, 1H), 7.49 (d,1H), 7.69 (d, 1H), 7.83 (dd, 1H), 7.89 (d, 1H), 8.09 (d, 1H).

Example 183(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide

(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from5-acetylisoxazole-3-carboxylic acid (0.200 g, 1.292 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.3 g, 1.076 mmol). The product was purified by Flash-chromatography.Yield 16.09%. 1H-NMR (400 MHz; CDCl₃): δ 1.26 (d, 3H), 2.65 (s, 3H),4.26 (dd, 1H), 4.46 (dd, 1H), 4.61 (m, 1H), 6.64 (d, 1H), 7.29 (s, 1H),7.51 (d, 1H), 7.63 (dd, 1H), 7.85 (s, 1H), 8.04 (d, 1H).

Example 184N—((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)isoxazole-3-carboxamide

Sodium borohydride (0.012 g, 0.308 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C.(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide(0.064 g, 0.154 mmol) was added and the reaction mixture was warmedslowly to RT while stirring overnight. The crude product was cooled to0° C., the pH was adjusted below 7 and the mixture was evaporated. 5% ofDCM/MeOH was added and the crude product was washed with 1M NaHCO₃,water and dried. Yield 81%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H),1.40 (dd, 3H), 4.32 (d, 2H), 4.45 (m, 1H), 4.86 (m, 1H), 5.78 (dd, 1H),6.53 (dd, 1H), 7.00 (d, 1H), 7.84 (d, 1H), 7.86 (m, 1H), 7.98 (d, 1H),8.75 (d, 1H).

Example 185(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1H-pyrazol-3-yl)oxazole-4-carboxamidea) 2-Bromooxazole-4-carboxylic Acid

Ethyl 2-bromo-1,3-oxazole-4-carboxylate (2.5 g, 11.36 mmol) wasdissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (22.73ml, 22.73 mmol) was added slowly. The reaction mixture was stirred at RTfor 1 h, diluted with water and pH was adjusted to 2. Formed precipitatewas filtered and dried to yield the title compound (1.1 g). The filtratewas extracted three times with ethyl acetate. Ethyl acetate phases werecombined, dried and evaporated to dryness to yield the title compound0.85 g. Total yield 88%. m/z [192.0+1]

b)(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (741 mg,2.82 mmol) and 2-bromooxazole-4-carboxylic acid (850 mg, 3.41 mmol). Theproduct was purified by Flash-chromatography. Yield 12.4%. 1H-NMR (400MHz; CDCl₃): δ 1.20 (d, 3H), 4.18-4.47 (m, 2H), 4.51-4.65 (m, 1H), 6.64(d, 1H), 7.48 (d, 1H), 7.72 (dd, 1H), 7.92-7.99 (m, 3H), 8.21 (s, 1H).

c)N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)oxazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide(153 mg, 0.352 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronicacid pinacol ester (490 mg, 1.760 mmol),tetrakis(triphenyl-phosphine)palladium (4.07 mg, 3.52 umol), THF and 2 MNa₂CO₃ solution were added in a microwave flask and heated at 100° C.for 1 h. The reaction mixture was diluted with DCM and washed twice withNaHCO₃ solution. Organic phase was dried and evaporated to dryness. Theproduct was purified twice by Flash-chromatography. Yield 31.4%. m/z[506.0+1].

d)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1H-pyrazol-3-yl)oxazole-4-carboxamide

N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)oxazole-4-carboxamide(56 mg, 0.111 mmol) was added into a flask under nitrogen atmosphere.10% HCl/EtOH (0.126 ml, 0.277 mmol) was added and the reaction mixturewas stirred in RT for 2 h. The reaction mixture was diluted with ethylacetate and washed with 1M Na₂CO₃. The organic phase was dried, filteredand evaporated. The product was triturated using acetonitrile and THF,respectively. Yield 29.6%. 1H-NMR (400 MHz; CDCl₃): δ 1.27 (d, 3H), 4.31(dd, 1H), 4.43 (dd, 1H), 4.61 (m, 1H), 6.61 (d, 1H), 6.86 (d, 1H), 7.49(d, 1H), 7.60 (d, 1H), 7.66 (d, 1H), 7.72 (d, 1H), 7.87 (dd, 1H), 7.92(d, 1H), 8.23 (s, 1H), 10.78 (s, 1H).

Example 186N—((S)-1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide

Sodium borohydride (0.056 g, 1.477 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C.(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide(0.316 g, 0.738 mmol) was added and the reaction mixture was warmedslowly to RT while stirring overnight. The crude product was cooled to0° C., a few drops of water was added, the pH was adjusted below 7 andthe mixture was evaporated. 5% of DCM/MeOH was added and the crudeproduct was washed with 1M NaHCO₃, water and dried. Yield 68.1%. 1H-NMR(400 MHz; DMSO-d6): δ 1.13 (d, 3H), 1.40 (dd, 3H), 2.52 (s, 3H), 4.37(m, 2H), 4.48 (m, 1H), 4.92 (m, 1H), 6.24 (t, 1H), 6.62 (d, 1H), 7.63(d, 1H), 7.82 (d, 1H), 7.87 (dd, 1H), 8.10 (s, 1H), 8.37 (dd, 1H).

Example 187(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-isopropyl-1-(3-isopropyl-1H-pyrazole-5-carbonyl)-1H-pyrazole-5-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-isopropyl-1-(3-isopropyl-1H-pyrazole-5-carbonyl)-1H-pyrazole-5-carboxamidewas prepared using the method of Example 34(d) starting from3-isopropyl-1H-pyrazole-5-carboxylic acid (0.284 g, 1.841 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g,1.534 mmol). Yield 1.883%. 1H-NMR (400 MHz; CDCl₃): δ 1.23 (dd, 6H),1.27 (d, 3H), 1.32 (dd, 6H), 2.94 (m, 1H), 3.81 (m, 1H), 4.32 (dd, 1H),4.47 (dd, 1H), 4.63 (m, 1H), 6.63 (d, 1H), 6.81 (s, 1H), 7.08 (s, 1H),7.44 (d, 1H), 7.51 (d, 1H), 7.64 (dd, 1H), 7.78 (d, 1H), 7.80 (d, 1H).

Example 1883-Acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-3-hydroxypropyl)-1H-pyrazole-5-carboxamide

3-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-3-hydroxypropyl)-1H-pyrazole-5-carboxamidewas prepared using the method of Example 34(d) starting from3-acetyl-1H-pyrazole-5-carboxylic acid (84 mg, 0.542 mmol) and4-(1-(1-amino-3-hydroxypropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(125 mg, 0.452 mmol). The product was triturated using diethyl ether andacetonitrile, respectively. Yield 6.49%. 1H-NMR (400 MHz; MeOD): δ 2.51(s, 3H), 3.88 (m, 2H), 3.97 (dd, 1H), 4.03 (dd, 1H), 4.65 (m, 1H), 6.77(d, 1H), 7.21 (s, 1H), 7.75 (d, 1H), 7.79 (d, 1H), 7.91 (dd, 1H), 8.05(d, 1H).

Example 189(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-methoxyethylamino)thiazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide(0.2 g, 0.430 mmol) was added into a microwave vial with dry pyridine asa solvent under nitrogen atmosphere. 2-methoxyethylamine (0.187 ml,2.152 mmol) was added and the mixture was heated with microwaves at 120°C. Next day a total of 0.187 ml of 2-methoxyethylamine was added and thereaction mixture was heated for additional 3 h. The reaction mixture wasevaporated and the crude product dissolved in DCM, washed with Na₂CO₃,water and brine. The product was purified by Flash-chromatography. Yield38.5%. 1H-NMR (400 MHz; MeOD): δ 1.25 (d, 3H), 2.50 (s, 3H), 3.35 (s,3H), 3.40-3.43 (m, 2H), 3.46-3.49 (m, 2H), 4.34 (dd, 1H), 4.41 (dd, 1H),4.47-4.56 (m, 1H), 6.49 (d, 1H), 7.19 (s, 1H), 7.55 (d, 1H), 7.64 (dd,1H), 7.73 (d, 1H).

Example 190N—((S)-2-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propyl)-2-(1-hydroxyethyl)oxazole-4-carboxamidea)(S)-2-acetyl-N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propyl)oxazole-4-carboxamide

(S)-2-acetyl-N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propyl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from((S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(549 mg, 2.00 mmol) and 2-acetyloxazole-4-carboxylic acid (372 mg, 2.40mmol). The product was purified by Flash-chromatography. Yield 33.4%.1H-NMR (400 MHz; CDCl₃): δ 1.63 (d, 3H), 2.58 (d, 3H), 2.60 (s, 3H),3.78-3.98 (m, 2H), 4.60-4.71 (m, 1H), 6.44 (d, 1H), 7.44-7.62 (m, 4H),8.31 (s, 1H).

b)N—((S)-2-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propyl)-2-(1-hydroxyethyl)oxazole-4-carboxamide

Sodium borohydride (0.055 g, 1.462 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C.(S)-2-acetyl-N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propyl)oxazole-4-carboxamide(0.301 g, 0.731 mmol) was added and the reaction mixture was warmedslowly to RT while stirring overnight. The crude product was cooled to0° C., the pH was adjusted to 6 and the mixture was evaporated. 5% ofmethanol/DCM was added and the crude product was washed with 1M NaHCO₃and with water. The mixture was dried and evaporated. Yield 94%. ¹H-NMR(400 MHz; CDCl₃): δ 1.57 (d, 3H), 1.61 (d, 3H), 3.78-3.83 (m, 1H),3.87-3.94 (m, 1H), 4.59-4.68 (m, 1H), 4.87-4.96 (m, 1H), 6.43 (d, 1H),7.34-7.42 (m, 1H), 7.51 (d, 1H), 7.54-7.61 (m, 2H), 8.14 (s, 1H).

Example 191(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-methoxyethylamino)oxazole-4-carboxamidea)(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from((S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(742 mg, 2.70 mmol) and 2-bromooxazole-4-carboxylic acid (492 mg, 2.56mmol). The product was purified by Flash-chromatography. Yield 6.2%. m/z[448.7+1].

b)(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-methoxyethylamino)oxazole-4-carboxamide

(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide(0.180 g, 0.401 mmol) was added into a microwave vial with dry pyridineas a solvent. The mixture was bubbled with nitrogen. 2-Methoxyethylamine(0.129 ml, 2.407 mmol) was added and the mixture was heated withmicrowaves at 120° C. for 2 h. The product was purified byFlash-chromatography. Yield 15.65%. 1H-NMR (400 MHz; CDCl₃): δ 1.24 (d,3H), 2.58 (s, 3H), 3.39 (s, 3H), 3.44 (t, 2H), 3.51 (t, 2H), 4.30 (dd,1H), 4.40 (dd, 1H), 4.51-4.60 (m, 1H), 5.07 (t, 1H), 6.44 (d, 1H), 7.40(d, 1H), 7.51 (d, 1H), 7.52-7.58 (m, 2H), 7.67 (s, 1H).

Example 192(R)-5-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propyl)isoxazole-3-carboxamide

(R)-5-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from5-acetylisoxazole-3-carboxylic acid (0.314 g, 2.025 mmol) and(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(0.44 g, 1.688 mmol). The product was purified by Flash-chromatography.Yield 19.16%. 1H-NMR (400 MHz; CDCl₃): δ 1.63 (d, 3H), 2.63 (s, 3H),3.79-3.87 (m, 1H), 3.92-3.99 (m, 1H), 4.60-4.66 (m, 1H), 6.63 (d, 1H),7.29 (s, 1H), 7.50 (d, 1H), 7.69-7.74 (m, 2H), 7.82 (dd, 1H), 8.05 (d,1H).

Example 193(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-acetylthiazole-4-carboxylic acid (0.680 g, 3.49 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(0.8 g, 2.91 mmol). The product was purified by Flash-chromatography.Yield 30.0%. 1H-NMR (400 MHz; CDCl₃): δ 1.30 (d, 3H), 2.53 (s, 3H), 2.54(s, 3H), 4.35 (dd, 1H), 4.47 (dd, 1H), 4.61-4.69 (m, 1H), 6.44 (d, 1H),7.49-7.54 (m, 3H), 7.95 (d, 1H), 8.39 (s, 1H).

Example 194(S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)oxazole-4-carboxamide

(S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from2-amino-1,3-oxazole-4-carboxylic acid (343 mg, 2.68 mmol) and(S)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (613 mg,2.231 mmol). The product was triturated using diethyl ether. Yield4.32%. 1H-NMR (400 MHz; DMSO-d6): δ 0.86 (t, 3H), 1.41-1.51 (m, 2H),4.18-4.39 (m, 3H), 6.78 (s, 2H), 6.93 (d, 1H), 7.74 (d, 1H), 7.76 (s,1H), 7.79 (d, 1H), 7.94-8.00 (m, 2H), 8.08 (s, 1H).

Example 195(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-((2,5-dioxopyrrolidin-1-yl)methyl)oxazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(chloro-methyl)oxazole-4-carboxamide(0.132 g, 0.327 mmol) and potassium carbonate (0.068 g, 0.490 mmol) weredissolved in dry DMF under nitrogen atmosphere. Succinimide (0.036 g,0.359 mmol) was added and the mixture was stirred in RT for 4.5 h. DCMwas added and the organic phase was washed with water. The product wastriturated using diethyl ether, DCM and finally by Flash-chromatography.Yield 16.92%. %. 1H-NMR (400 MHz; CDCl₃): δ 1.23 (d, 3H), 2.83 (s, 4H),4.29 (dd, 1H), 4.39 (dd, 1H), 4.51-4.59 (m, 1H), 4.83 (s, 2H), 6.63 (d,1H), 7.47 (d, 1H), 7.52 (d, 1H), 7.74 (d, 1H), 7.87 (dd, 1H), 7.98 (d,1H), 8.11 (s, 1H).

Example 196N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)oxazole-4-carboxamidea)(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide

(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-oxazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (600 mg,2.301 mmol) and 2-acetyloxazole-4-carboxylic acid (428 mg, 2.76 mmol).The product was purified by Flash-chromatography. Yield 11.6%. 1H-NMR(400 MHz; CDCl₃): δ 1.26 (d, 3H), 2.68 (s, 3H), 4.26-4.33 (m, 1H),4.40-4.47 (m, 1H), 4.55-4.68 (m, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.67(d, 1H), 7.72 (d, 1H), 7.88 (dd, 1H), 7.93 (d, 1H), 8.31 (s, 1H).

b)N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)oxazole-4-carboxamide

Sodium borohydride (0.019 g, 0.498 mmol) was added into a flask and theatmosphere was replaced with nitrogen. Dry ethanol was added and thereaction mixture was cooled to 0° C.(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide(0.099 g, 0 0.249 mmol) was added and the reaction mixture was warmedslowly to RT while stirring overnight. The crude product was cooled to0° C., the pH was adjusted to 6 and the mixture was evaporated. 5% ofDCM/MeOH was added and the crude product was washed with 1M NaHCO₃,water and dried. Yield 89%. 1H-NMR (400 MHz; CDCl₃): δ 1.22 (d, 3H),1.63 (d, 3H), 2.51 (s, 1H), 4.25-4.31 (m, 1H), 4.41 (dd, 1H), 4.54-4.63(m, 1H), 5.00 (q, 1H), 6.61 (d, 1H), 7.49 (d, 1H), 7.68 (d, 1H), 7.70(d, 1H), 7.86-7.89 (m, 1H), 7.95-7.96 (m, 1H), 8.15 (s, 1H).

Example 197(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((2,5-dioxopyrrolidin-1-yl)methyl)isoxazole-3-carboxamidea)(S)-5-(bromomethyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)isoxazole-3-carboxamide

5-(Bromomethyl)isoxazole-3-carboxylic acid (1.027 g, 4.99 mmol) and DCC(1.029 g, 4.99 mmol) were dissolved in dry DCM under nitrogen atmosphereand (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.0g, 3.84 mmol) was added. The mixture was stirred overnight at RT and aprecipitate was filtered. The filtrate was washed with water, dried andevaporated to dryness. The evaporation residue was purified byFlash-chromatography to give the title compound. Yield 83%. 1H-NMR (400MHz; DMSO): δ 1.17 (d, 3H), 4.32 (d, 2H), 4.40-4.50 (m, 1H), 4.86 (s,2H), 6.81 (s, 1H), 6.94 (d, 1H), 7.82 (d, 1H), 7.91 (dd, 1H), 7.97 (dd,1H), 8.08 (dd, 1H). 8.85 (d, 1H)

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((2,5-dioxopyrrolidin-1-yl)methyl)isoxazole-3-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((2,5-dioxopyrrolidin-1-yl)methyl)isoxazole-3-carboxamidewas prepared using the method of Example 195 starting from(S)-5-(bromomethyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide(262 mg, 0.584 mmol). The product was purified by Flash-chromatography.Yield 89%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 2.57 (s, 4H),4.28-4.43 (m, 2H), 4.52-4.63 (m, 1H), 4.85 (s, 2H), 6.63 (s vai d, 1H),6.71 (d, 1H), 7.65 (d, 1H), 7.68 (d, 1H), 7.75 (d, 1H), 7.85 (dd, 1H),8.06 (d, 1H).

Example 198(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(300 mg, 1.092 mmol) and 2-(methylamino)thiazole-4-carboxylic acidhydrochloride (314 mg, 1.613 mmol). The product was purified twice byFlash-chromatography (normal phase and reverse phase). Yield 4.86%.1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.56 (s, 3H), 2.93 (d, 3H),4.28-4.43 (m, 2H), 4.47-4.61 (m, 1H), 5.04-5.12 (m, 1H), 6.43 (d, 1H),7.31 (d, 1H), 7.49-7.56 (m, 3H), 7.67 (m, 1H).

Example 199(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(morpholinomethyl)isoxazole-3-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(morpholinomethyl)isoxazole-3-carboxamidewas was prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.690 mmol) and 5-(morpholinomethyl)isoxazole-3-carboxylic acidhydrochloride (206 mg, 0.828 mmol). The product was purified by reversephase Flash-chromatography. Yield 16.9%. 1H-NMR (400 MHz; MeOD): δ 1.26(d, 3H), 2.47-2.56 (m, 4H), 3.65-3.71 (m, 4H), 3.75 (d, 2H), 4.28-4.44(m, 2H), 4.53-4.63 (m, 1H), 6.59 (t, 1H), 6.77 (d, 1H), 7.71 (d, 1H),7.78 (dd, 1H), 7.88 (dd, 1H), 8.08 (dd, 1H).

Example 200(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-methyl-1H-imidazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-methyl-1H-imidazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile(300 mg, 1.092 mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (207mg, 1.638 mmol). The product was purified twice by Flash-chromatography(normal phase and reverse phase). Yield 38.7%. 1H-NMR (400 MHz; CDCl3):δ 1.26 (d, 3H), 2.56 (s, 3H), 3.74 (s, 3H), 4.30-4.43 (m, 2H), 4.49-4.61(m, 1H), 6.41 (d, 1H), 7.35 (d, 1H), 7.39 (d, 1H), 7.49-7.56 (m, 3H),7.60 (d, 1H).

Example 201(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-isopropylisoxazole-3-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-isopropylisoxazole-3-carboxamidecarboxamide was prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (150 mg,0.575 mmol) and 5-isopropylisoxazole-3-carboxylic acid (98 mg, 0.633mmol). The product was purified by Flash-chromatography and trituratedusing methanol. Yield 7.86%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H),1.33 (d, 6H), 3.06-3.19 (m, 1H), 4.26 (dd, 1H), 4.43 (dd, 1H), 4.52-4.64(m, 1H), 6.40 (d, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.69 (d, 1H), 7.80(d, 1H), 7.84 (dd, 1H), 8.06 (s, 1H).

Example 202(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)isoxazole-3-carboxamidea)(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile

2-chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (5.0 g, 22.56 mmol),N-t-BOC—(R)-1-amino-2-propanol (7.91 g, 45.1 mmol) andtriphenylphosphine (11.84 g, 45.1 mmol) were dissolved in dry ethylacetate under nitrogen atmosphere and stirred. DIAD (9.12 g, 45.1 mmol)was added dropwise and the reaction flask was cooled by ice bath. Thereaction was stirred at RT overnight. Water and concentrated HCl (18.53ml, 226 mmol) were added to the reaction mixture and the reaction wasstirred at RT overnight. Water and DCM were added to the reactionmixture, stirred and water phase was separated. Organic phase wasextracted twice with water and water phases were combined. The combinedwater phase was washed twice with DCM and pH of water was adjusted to˜12 by addition of NaOH. Water phase was extracted twice with DCM andcombined DCM phase was washed twice with water. Organic phase wasevaporated to dryness and the product was purified byFlash-chromatography. Yield 31.8%. 1H-NMR (400 MHz; DMSO): δ 1.42 (d,3H), 2.80-3.00 (m, 2H), 4.27-4.38 (m, 1H), 7.03 (d, 1H), 7.84-7.95 (m,2H), 8.00 (m, 1H).

b)(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)isoxazole-3-carboxamide

(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propyl)isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(500 mg, 1.794 mmol) and 5-acetylisoxazole-3-carboxylic acid (417 mg,2.69 mmol). The product was purified twice by Flash-chromatography(normal phase and reverse phase). Yield 19.6%. 1H-NMR (400 MHz; DMSO): δ1.51 (d, 3H), 2.57 (s, 3H), 3.56-3.77 (m, 2H), 4.65-4.77 (m, 1H), 7.01(d, 1H), 7.56 (s, 1H), 7.89 (dd, 1H), 7.91 (d, 1H), 7.98 (s, 1H), 9.03(t, 1H).

Example 203(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(5-methylfuran-2-yl)isoxazole-3-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(5-methylfuran-2-yl)isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (150 mg,0.575 mmol) and 5-(5-methyl-furan-2-yl)-isoxazole-3-carboxylic acid (111mg, 0.575 mmol). The product was purified by Flash-chromatography. Yield41.5%. 1H-NMR (400 MHz; MeOD): δ 1.28 (d, 3H), 2.38 (dd, 3H), 4.27-4.45(m, 2H), 4.54-4.63 (m, 1H), 6.23-6.26 (m, 1H), 6.66 (s, 1H), 6.77 (d,1H), 6.91 (td, 1H), 7.71 (d, 1H), 7.75 (dd, 1H), 7.86 (dd, 1H), 8.05(dd, 1H).

Example 204(S)—N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2-methyl-1H-imidazole-4-carboxamide

(S)—N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2-methyl-1H-imidazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(1.0 g, 3.59 mmol) and 2-methyl-1H-imidazole-4-carboxylic acid (0.498 g,3.95 mmol). The product was purified twice by Flash-chromatography(normal phase and reverse phase). Yield 8.2%. 1H-NMR (400 MHz; DMSO): δ1.45 (d, 3H), 2.27 (s, 3H), 3.50-3.74 (m, 2H), 4.62-4.77 (m, 1H), 7.02(d, 1H), 7.45 (s, 1H), 7.88-8.04 (m, 4H), 12.11 (s, 1H).

Example 205(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

1H-Pyrazole-4-carbothioic acid amide (300 mg, 2.359 mmol) and3-bromo-2-oxopropanoic acid (433 mg, 2.60 mmol) were dissolved in dryTHF under nitrogen atmosphere. The reaction mixture was heated at 60° C.for 3 h. The reaction mixture was cooled to RT and evaporated todryness. (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(300 mg, 1.151 mmol) and DCM were added to the reaction flask and thetitle compound was prepared using the method of Example 34(d). Theproduct was purified by Flash-chromatography and triturated usingmethanol. Yield 13.7%. 1H-NMR (400 MHz; DMSO): δ 1.17 (d, 3H), 4.31-4.54(m, 3H), 6.96 (d, 1H), 7.84 (d, 1H), 7.87 (d, 1H), 7.94 (dd, 1H), 8.00(bs, 1H), 8.06 (d, 1H), 8.08 (d, 1H), 8.38 (d, 1H), 8.40 (bs, 1H), 13.38(s, 1H).

Example 206(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

1H-Pyrazole-4-carbothioic acid amide (1.0 g, 7.86 mmol) and3-bromo-2-oxopropanoic acid (1.44 g, 8.65 mmol) were dissolved in dryTHF under nitrogen atmosphere. The reaction mixture was heated at 60° C.for 4.5 h. The reaction mixture was cooled to RT and evaporated todryness. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(1.367 g, 5.24 mmol) and DCM were added to the reaction flask and thetitle compound was prepared using the method of Example 34(d). Theproduct purified by Flash-chromatography and triturated usingacetonitrile. Yield 37.7%. 1H-NMR (400 MHz; DMSO): δ 1.11 (d, 3H),4.25-4.48 (m, 3H), 6.89 (d, 1H), 7.77 (d, 1H), 7.80 (d, 1H), 7.87 (dd,1H), 7.93 (bs, 1H), 7.99 (d, 1H), 8.01 (s, 1H), 8.31 (d, 1H), 8.33 (bs,1H), 13.31 (bs, 1H).

Example 207N—((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

Sodium borohydride (8.21 mg, 0.217 mmol) was added into a flask undernitrogen atmosphere. Dry ethanol was added and the mixture was stirred.(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide(45 mg, 0.108 mmol) in dry ethanol was added slowly and the mixture wasstirred at RT for 2.5 h. pH of the reaction mixture was adjusted to ˜2by addition of 1M HCl and the mixture was evaporated to dryness. Theproduct was purified by Flash-chromatography. Yield 57.5%. 1H-NMR (400MHz; DMSO): δ 1.13 (d, 3H), 1.37 (d, 3H), 4.22-4-51 (m, 3H), 4.73-4.85(m, 1H), 5.38 (d, 1H), 6.39 (s, 1H), 6.99 (d, 1H), 7.82 (d, 1H), 7.86(d, 1H), 7.97 (d, 1H), 8.09 (d, 1H), 13.00 (s, 1H)

Example 208(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-methoxyisoxazole-5-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-methoxyisoxazole-5-carboxamidecarboxamide was prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (350 mg,1.342 mmol) and 3-methoxy-isoxazole-5-carboxylic acid (250 mg, 1.745mmol). The product was purified by Flash-chromatography. Yield 66.0%.1H-NMR (400 MHz; MeOD): δ 1.28 (d, 3H), 3.98 (s, 3H), 4.26-4.42 (m, 2H),4.49-4.60 (m, 1H), 6.50 (s, 1H), 6.77 (d, 1H), 7.69 (d, 1H), 7.77 (dd,1H), 7.86 (dd, 1H), 8.01 (dd, 1H).

Example 209(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(hydroxymethyl)isoxazole-3-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(hydroxymethyl)isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.675 mmol) and 5-(hydroxymethyl)isoxazole-3-carboxylic acid (126 mg,0.878 mmol). The product purified twice by Flash-chromatography (normalphase and reverse phase) and triturated using diethyl ether. Yield 1.9%.1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 4.28-4-43 (m, 2H), 4.52-4.63 (m,1H), 4.68 (d, 2H), 6.57 (t, 1H), 6.77 (d, 1H), 7.70 (d, 1H), 7.78 (dd,1H), 7.88 (dd, 1H), 8.07 (dd, 1H).

Example 210(R)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamidea)(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile

(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrilewas prepared using the method of Example 202 starting from2-chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (5.0 g, 22.56 mmol)and (R)-tert-butyl (1-hydroxypropan-2-yl)carbamate (7.91 g, 45.1 mmol).The product was evaporated to dryness. Yield 70.5%. 1H-NMR (400 MHz;DMSO): δ 0.96 (d, 3H), 3.20-3.30 (m, 1H), 4.00-4.10 (m, 2H), 7.03 (d,1H), 7.85-7.91 (m, 2H), 7.99 (m, 1H).

b)(R)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide

(R)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(1.0 g, 3.59 mmol) and 2-methyl-1H-imidazole-4-carboxylic acid (0.50 g,3.95 mmol). The product purified twice by Flash-chromatography (normalphase and reverse phase). Yield 10.4%. 1H-NMR (400 MHz; DMSO): δ 1.07(d, 3H), 2.30 (s, 3H), 4.22-4.50 (m, 3H), 7.02 (d, 2H), 7.42 (d, 1H),7.86 (d, 1H), 7.93 (dd, 1H), 8.00 (d, 1H), 8.07 (d, 1H), 12.11 (bs, 1H).

Example 211(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.652 mmol) and 5-methyl-1,3,4-oxadiazole-2-carboxylic acid (100 mg,0.782 mmol). The product was purified twice by Flash-chromatography(normal phase and reverse phase). Yield 3.7%. 1H-NMR (400 MHz; MeOD): δ1.28 (d, 3H), 2.58 (s, 3H), 4.30-4.44 (m, 2H), 4.53-4.64 (m, 1H),6.76-6.78 (m, 1H), 7.71 (d, 1H), 7.76-7.80 (m, 1H), 7.86-7.90 (m, 1H),8.02-8.04 (m, 1H).

Example 212N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-ethoxyethyl)thiazole-4-carboxamidea) 2-(1-ethoxyethyl)thiazole-4-carboxylic Acid

Potassium hydroxide (0.277 g, 4.93 mmol) and ethanol were added to aflask and stirred. 2-Bromopropionamide (0.5 g, 3.29 mmol) was added andthe reaction mixture was stirred overnight. The mixture was filtratedand the filtrate was evaporated to dryness.2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawensson's reagent) (0.665 g, 1.643 mmol) and THF were added to theevaporation residue and the mixture was heated to 60° C. for 2 h. Thereaction mixture was evaporated to dryness. 3-Bromopyruvic acid (0.604g, 3.62 mmol) and THF were added to the evaporation residue and themixture was heated to 60° C. for 3 h. The reaction mixture was cooled toRT and evaporated to dryness. The product was purified byFlash-chromatography. Yield 102%. 1H-NMR (400 MHz; DMSO): δ 1.16 (t,3H), 1.46 (d, 3H), 3.79-3.86 (m, 2H), 4.78 (q, 1H), 8.42 (s, 1H).

b)N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-ethoxyethyl)thiazole-4-carboxamide

N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-ethoxyethyl)thiazole-4-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (350 mg,1.342 mmol) and 2-(1-ethoxyethyl)thiazole-4-carboxylic acid (661 mg,3.28 mmol). The product purified by Flash-chromatography (reversephase). Yield 31.7%. 1H-NMR (400 MHz; MeOD): δ 1.19-1.24 (m, 3H), 1.26(dd, 3H), 1.51 (t, 3H), 3.48-3.58 (m, 1H), 3.58-3.66 (m, 1H), 4.33-4.46(m, 2H), 4.52-4.62 (m, 1H), 4.72-4.79 (m, 1H), 6.77 (dd, 1H), 7.70-7.72(m, 1H), 7.75-7.79 (m, 1H), 7.85-7.89 (m, 1H), 8.02 (m, 1H), 8.08 (d,1H).

Example 213(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(methylsulfonamidomethyl)isoxazole-3-carboxamidea)(S)-5-(aminomethyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(methylsulfonamidomethyl)isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (300 mg,1.151 mmol) and5-{[(tert-butoxycarbonyl)amino]methyl}-isoxazole-3-carboxylic acid (362mg, 1.496 mmol). The reaction mixture was washed twice with water, driedand evaporated to dryness. 10% HCl/ethanol solution (5.2 ml) was addedto this evaporation residue and the mixture was stirred at RT overnight.The reaction mixture was evaporated, DCM and water were added and pH ofwater phase was adjusted to ˜7 by addition of 5% of NaHCO₃. Organicphase was separated, washed with water and evaporated to dryness toafford the title compound. The product was purified byFlash-chromatography. Yield 14.5%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d,3H), 3.93 (d, 2H), 4.28-4.43 (m, 2H), 4.53-4.63 (m, 1H), 6.55 (t, 1H),6.76 (d, 1H), 7.70 (d, 1H), 7.78 (dd, 1H), 7.89 (dd, 1H), 8.07 (dd, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(methylsulfonamidomethyl)isoxazole-3-carboxamide

(S)-5-(aminomethyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide(25 mg, 0.065 mmol) and DCM were added to a flask and stirred undernitrogen atmosphere. Methanesulfonyl chloride (9.05 μl, 0.065 mmol) wasadded and the reaction mixture was stirred at RT for 1 h.Methanesulfonyl chloride (6 μl) was added and the reaction mixture wasstirred at RT overnight. Methanesulfonyl chloride (16 μl) was added andthe reaction mixture was stirred at RT for 3 days. The reaction mixturewas evaporated to dryness and the product was triturated usingacetonitrile. Yield 8.3%. 1H-NMR (400 MHz; DMSO): δ 1.16 (d, 3H), 2.94(s, 3H), 4.26-4.53 (m, 5H), 6.64 (s, 1H), 6.94 (d, 1H), 7.82 (d, 1H),7.86 (m, 1H), 7.92 (dd, 1H), 7.98 (d, 1H), 8.09 (d, 1H), 8.81 (d, 1H)

Example 214(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-methyl-1H-pyrazol-5-yl)isoxazole-3-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-methyl-1H-pyrazol-5-yl)isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.69 mmol) and 5-(1-methyl-1H-pyrazol-5-yl)isoxazole-3-carboxylic acid(173 mg, 0.898 mmol). The product was purified by triturated usingacetonitrile and methanol. Yield 28.2%. 1H-NMR (400 MHz; DMSO): δ 1.19(d, 3H), 4.06 (s, 3H), 4.35 (d, 2H), 4.43-4.57 (m, 1H), 6.91 (d, 1H),6.96 (d, 1H), 7.20 (s, 1H), 7.59 (d, 1H), 7.85 (d, 1H), 7.93 (dd, 1H),7.97 (d, 1H), 8.09 (d, 1H), 8.94 (d, 1H).

Example 215(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxycyclopentyl)isoxazole-3-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxycyclopentyl)isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.69 mmol) and 5-(1-hydroxycyclopentyl)isoxazole-3-carboxylic acid (173mg, 0.878 mmol). The product purified twice by Flash-chromatography(normal phase and reverse phase). Yield 23.2%. 1H-NMR (400 MHz; MeOD): δ1.26 (d, 3H), 1.75-2.12 (m, 8H), 4.28-4.44 (m, 2H), 4.52-4.64 (m, 1H),6.51 (s, 1H), 6.77 (d, 1H), 7.70 (d, 1H), 7.77 (dd, 1H), 7.88 (dd, 1H),8.09 (dd, 1H).

Example 216(S)-5-tert-butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide

(S)-5-tert-butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamidewas prepared using the method of Example 34(d) starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.69 mmol) and 5-tert-butylisoxazole-3-carboxylic acid (132 mg, 0.782mmol). The product was purified by Flash-chromatography (reverse phase).Yield 53.6%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 1.35 (s, 9H),4.26-4.45 (m, 2H), 4.51-4.63 (m, 1H), 6.34 (s, 1H), 6.77 (d, 1H), 7.70(d, 1H), 7.77 (dd, 1H), 7.87 (dd, 1H), 8.09 (dd, 1H).

Example 217(S)-3-acetyl-N-(2-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-propyl)-1H-pyrazole-5-carboxamidea) (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile

The title compound was prepared from4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-benzonitrile (1.4 g, 5.90 mmol),(R)-tert-butyl 2-hydroxypropylcarbamate (1.03 g, 5.90 mmol),triphenylphosphine (2.32 g, 8.85 mmol) and di-tert-butylazodicarboxylate (2.04 g, 8.85 mmol) using the method of Example 34(c).Yield 0.429 g. ¹H NMR (400 MHz; MeOD): δ 1.52 (d, 3H), 2.98 (dd, 1H),3.12 (dd, 1H), 4.43 (m, 1H), 6.87 (d, 1H), 7.77 (d, 1H), 7.98 (m, 1H),8.21 (m, 1H), 8.33 (m, 1H).

b)(S)-3-acetyl-N-(2-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile(429 mg, 1.45 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (225 mg,1.45 mmol), HOBt (236 mg, 1.75 mmol), DIPEA (0.305 mL, 1.75 mmol) andEDCI (335 mg, 1.75 mmol) using DCM as solvent using the method ofExample 34(d) affording 483 mg of the title compound. ¹H NMR (400 MHz;d₆-DMSO): δ 1.50 (d, 3H), 2.47 (s, 3H), 3.63 (m, 2H), 4.69 (m, 1H), 7.03(d, 1H), 7.25 (bs, 1H), 7.90 (d, 1H), 8.18 (m, 2H), 8.27 (m, 1H), 14.15(bs, 1H).

Example 218(R)-3-acetyl-N-(2-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-propyl)-1H-pyrazole-5-carboxamidea)(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile

The title compound was obtained from4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-benzonitrile (1.32 g, 5.55mmol), (S)-tert-butyl 2-hydroxypropylcarbamate (0.97 g, 5.55 mmol),triphenyl phosphine (2.18 g, 8.33 mmol), di-tert-butyl azodicarboxylate(1.92 g, 8.33 mmol) using the method of Example 34(c). Yield 0.381 g. ¹HNMR (400 MHz; MeOD): δ 1.52 (d, 3H), 2.98 (dd, 1H), 3.12 (dd, 1H), 4.43(m, 1H), 6.87 (d, 1H), 7.77 (d, 1H), 7.98 (m, 1H), 8.21 (m, 1H), 8.33(m, 1H).

b)(R)-3-acetyl-N-(2-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile(381 mg, 1.3 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (200 mg, 1.3mmol), HOBt (210 mg, 1.55 mmol), DIPEA (0.271 mL, 1.55 mmol) and EDCI(298 mg, 1.55 mmol) using DCM as solvent using the method of Example34(d) affording 410 mg of the title compound. ¹H NMR (400 MHz; d₆-DMSO):δ 1.50 (d, 3H), 2.47 (s, 3H), 3.63 (m, 2H), 4.69 (m, 1H), 7.03 (d, 1H),7.25 (bs, 1H), 7.90 (d, 1H), 8.18 (m, 2H), 8.27 (m, 1H), 14.15 (bs, 1H).

Example 219(S)-3-acetyl-N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile(380 mg, 1.45 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (229 mg,1.48 mmol) using the method of Example 34(d). Yield 249 mg. ¹H NMR (400MHz; d₆-DMSO): δ 1.49 (d, 3H), 2.48 (s, 3H), 3.62 (m, 2H), 4.67 (m, 1H),6.98 (d, 1H), 7.25 (bs, 1H), 7.76 (m, 2H), 7.89 (d, 1H), 8.52 (bs, 1H),14.18 (bs, 1H).

Example 220N—((R)-2-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propyl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

(R)-3-acetyl-N-(2-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide of Example 218 (0.1 g, 0.232 mmol) wasreacted with sodium borohydride (0.018 g, 0.465 mmol) using the methodof Example 84. Yield of the title compound 0.059 g. ¹H NMR (400 MHz;CDCl₃): δ 1.55 (d, 3H), 1.61 (d, 3H), 3.77 (m, 1H), 3.90 (m, 1H), 4.64(m, 1H), 5.03 (q, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 7.44 (bs, 1H), 7.51(d, 1H), 7.83 (d, 1H), 8.06 (dd, 1H), 8.32 (s, 1H), 10.40 (bs, 1H).

Example 221 (R)-2-amino-N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl) thiazole-4-carboxamide

The title compound was synthesized from(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile(380 mg, 1.45 mmol), 2-aminothiazole-4-carboxylic acid (217 mg, 1.5mmol), HOBt (235 mg, 1.74 mmol), DIPEA (0.303 mL, 1.74 mmol) and EDCI(333 mg, 1.74 mmol) using DCM as solvent using the method of Example34(d). Yield 92 mg. ¹H NMR (400 MHz; CDCl₃): δ 1.60 (d, 3H), 3.81 (m,2H), 4.61 (m, 1H), 4.91 (s, 2H), 6.60 (d, 1H), 7.37 (s, 1H), 7.50 (d,1H), 7.58 (m, 2H), 7.80 (m, 1H).

Example 222(R)—N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-2-(cyanomethyl)thiazole-4-carboxamidea) 2-(cyanomethyl)thiazole-4-carboxylic Acid

(Cyano)thioacetamide (2 g, 19.97 mmol) was stirred in excess THF (40 mL)under nitrogen atmosphere. The solution was cooled to 0° C. and thesolution of 3-bromopyruvic acid (3.33 g, 19.97 mmol) dissolved in 5 mLTHF was added drop-wise. The mixture was refluxed for 3 h. Solvent wasevaporated and the crude product was purified by flash chromatography(silica, eluent: 0-40% DCM-10% MeOH/DCM mixture) to yield 1.615 g of thetitle compound. ¹H NMR (400 MHz; CDCl₃): δ 4.20 (s, 2H), 8.33 (s, 1H).

b)(R)—N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-2-(cyanomethyl)thiazole-4-carboxamide

The title compound was prepared from(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile(380 mg, 1.45 mmol) and 2-(cyanomethyl)-thiazole-4-carboxylic acid (244mg, 1.45 mmol) using the method of Example 34(d). Yield 70 mg. ¹H NMR(400 MHz; d₆-DMSO): δ 1.47 (d, 3H), 3.29 (s, 2H), 3.67 (m, 2H), 4.74 (m,1H), 6.99 (d, 1H), 7.77 (m, 2H), 7.92 (d, 1H), 8.25 (d, 1H), 8.44 (m,1H).

Example 223N—((R)-1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamidea) (R)-3-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared from(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (733mg, 2.79 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (431 mg, 2.79mmol) using the method of Example 34(d). Yield 121 mg. ¹H NMR (400 MHz;d₆-DMSO): δ 1.49 (d, 3H), 2.48 (s, 3H), 3.63 (m, 2H), 4.67 (m, 1H), 6.98(d, 1H), 7.25 (bs, 1H), 7.76 (m, 2H), 7.89 (d, 1H), 14.16 (s, 1H).

b)N—((R)-1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

The title compound was prepared from(R)-3-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide(90 mg, 0.226 mmol) and sodium tetrahydroborate (17 mg, 0.452 mmol)using the method of Example 84. Yield 41 mg. ¹H NMR (400 MHz; CDCl₃): δ1.57 (d, 3H), 1.59 (d, 3H), 4.26 (m, 1H), 4.45 (m, 1H), 4.58 (m, 1H),5.06 (q, 1H), 6.61 (m, 2H), 7.50 (d, 1H), 7.58 (m, 2H), 7.73 (bs, 1H),10.44 (s, 1H).

Example 224(S)-3-acetyl-N-(1-(4-chloro-3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-1H-pyrazole-5-carboxamidea) 2-chloro-4-(4-chloro-1H-pyrazol-5-yl)benzonitrile Hydrochloride

2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile(12.0 g, 41.7 mmol) was dissolved in acetic acid (20 ml) and sodiumhypochlorite solution (29.0 ml, 416 mmol) was added. The reactionmixture was stirred at RT overnight. Further again, acetic acid (120 ml)and sodium hypochlorite solution (14 ml) were added and the mixture wasstirred at RT overnight. The precipitate was filtrated and washed withwater and DCM. The precipitate was dried in vacuum 40° C. overnight toyield 5.8 grams of 2-chloro-4-(4-chloro-1H-pyrazol-5-yl)benzonitrile.The mixture of 2-chloro-4-(4-chloro-1H-pyrazol-5-yl)benzonitrile (5.8 g,24.36 mmol) and 10% HCl/ethanol solution (167 ml, 365 mmol) was stirredfor 2 h at RT and the precipitate was filtrated and washed with water.The precipitate was silted up with ethanol to yield 4.0 g of the rawmaterial. The product was purified with Flash-chromatography to yieldtotal 18% of the title compound. ¹H NMR (400 MHz; d₆-DMSO): δ 8.05 (m,2H), 8.16 (m, 2H).

b)(S)-4-(1-(2-aminopropyl)-4-chloro-1H-pyrazol-3-yl)-2-chlorobenzonitrile

The title compound was prepared from2-chloro-4-(4-chloro-1H-pyrazol-5-yl)benzonitrile (0.690 g, 2.9 mmol),(S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (0.508 g, 2.9),triphenylphosphine (1.14 g, 4.35 mmol) and di-tert-butylazodicarboxylate (1 g, 4.35 mmol) using the method of Example 34(c).Yield 0.518 g. ¹H NMR (400 MHz; CDCl₃): δ 1.16 (d, 3H), 1.32 (bs, 2H),3.47 (m, 1H), 3.88 (dd, 1H), 4.09 (dd, 1H), 7.56 (s, 1H), 7.69 (d, 1H),7.99 (dd, 1H), 8.13 (d, 1H).

c)(S)-3-acetyl-N-(1-(4-chloro-3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from(S)-4-(1-(2-aminopropyl)-4-chloro-1H-pyrazol-3-yl)-2-chlorobenzonitrile(518 mg, 1.75 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (270 mg,1.75 mmol), HOBt (285 mg, 2.1 mmol), DIPEA (0.367 mL, 2.1 mmol) and EDCI(404 mg, 2.1 mmol) using DCM as solvent using the method of Example34(d) to afford 382 mg of the title compound. ¹H NMR (400 MHz; d₆-DMSO):δ 1.15 (d, 3H), 2.42 (s, 3H), 4.30 (m, 2H), 4.44 (m, 1H), 6.86 (s, 1H),8.01 (m, 3H), 8.12 (s, 1H).

Example 226(S)—N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamidea) Ethyl 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate

Sodium (0.2 g, 13.69 mmol) was dissolved completely in 12 mL of ethanolunder nitrogen atmosphere. To this solution was added 3-acetylpyridine(1.499 ml, 13.69 mmol) followed by diethyl oxalate (1.859 ml, 13.69mmol) at RT with constant stirring. The mixture was then warmed to 75°C. for 3 h. The mixture was then cooled to RT and a solution ofhydrazine hydrochloride (0.938 g, 13.69 mmol) in water (2 ml) was added.Further again the solution was warmed to 75° C. for 3 h. After thecompletion of the reaction as evidenced from the LC-MS, the reactionmixture was cooled and neutralized by 2 M NaOH solution. The crudeproduct was then extracted with ethyl acetate, washed with water andbrine. The organic solvent was evaporated and the residue was purifiedby CombiFlash (eluent: DCM: 10% MeOH/DCM). Yield 1.577 g. ¹H NMR (400MHz; MeOD): δ 1.40 (t, 3H), 4.39 (q, 2H), 7.29 (s, 1H), 7.51 (m, 1H),8.24 (m, 1H), 8.51 (dd, 1H), 8.99 (d, 1H).

b) 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic Acid

Ethyl 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (1.577 g, 7.26 mmol) inEthanol (60 ml) and THF (60 ml) was reacted with 1M NaOH solution (40ml, 7.26 mmol) and heated to 60° C. for 2 h. The solvents wereevaporated under reduced pressure and the residue was diluted withwater. The solution was made acidic by the addition of 2 N HCl solution.The resultant mixture was stirred in ice-cold bath for 4 h and the solidprecipitated was filtered, dried and weighed. Yield 378 mg. ¹H NMR (400MHz; d₆-DMSO): δ 7.39 (m, 2H), 8.21 (d, 1H), 8.53 (bs, 1H), 9.06 (bs,1H).

c)(S)—N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile(0.277 g, 1.06 mmol), 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid(0.2 g, 1.06 mmol), HOBt (0.17 g, 1.27 mmol), DIPEA (0.22 mL, 1.27 mmol)and EDCI (0.243 g, 1.27 mmol) using DCM as the solvent using the methodof Example 34(d). Yield 0.13 g. 1H NMR (400 MHz; d₆-DMSO): δ 1.50 (d,3H), 3.66 (m, 2H), 4.72 (m, 1H), 7.00 (d, 1H), 7.20 (s, 1H), 7.48 (m,1H), 7.78 (m, 2H), 7.93 (d, 1H), 8.13 (m, 1H), 8.55 (dd, 1H), 8.97 (s,1H).

Example 226(R)-5-acetyl-N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)isoxazole-3-carboxamide a)(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile

The title compound was obtained from2,6-difluoro-4-(1H-pyrazol-5-yl)-benzonitrile (3.88 g, 18.9 mmol),(S)-tert-butyl 2-hydroxypropylcarbamate (3.31 g, 18.9 mmol), triphenylphosphine (7.44 g, 28.4 mmol), di-tert-butyl azodicarboxylate (6.53 g,28.4 mmol) using the method of Example 34(c). Yield 2.29 g. ¹H NMR (400MHz; MeOD): δ 1.51 (d, 3H), 2.98 (dd, 1H), 3.12 (m, 1H), 4.42 (m, 1H),6.84 (d, 1H), 7.67 (m, 2H), 7.76 (d, 1H).

b)(R)-5-acetyl-N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)isoxazole-3-carboxamide

The title compound was synthesized from(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile(0.955 g, 3.64 mmol), 5-acetylisoxazole-3-carboxylic acid (0.565 g, 3.64mmol), HOBt (0.738 g, 5.46 mmol), DIPEA (1.9 mL, 10.92 mmol) and EDCI(1.05 g, 5.46 mmol) using DMF (10 mL) as solvent using the method ofExample 34(d). The product was purified with CombiFlash to afford 60 mgof pure product. ¹H NMR (400 MHz; CDCl₃): δ 1.63 (d, 3H), 2.64 (s, 3H),3.82 (m, 1H), 3.95 (m, 1H), 4.64 (m, 1H), 6.61 (d, 1H), 7.29 (s, 1H),7.52 (m, 3H), 7.62 (m, 1H).

Example 227(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamidea) 2-chloro-3-fluoro-4-(1H-pyrazol-5-yl)benzonitrile

The title compound was prepared from2-chloro-3-fluoro-4-iodobenzonitrile (0.242 g, 0.86 mmol) and1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester(0.239 g, 0.86 mmol) using the method of Example 34 (a) and (b). Yield0.075 g. ¹H NMR (400 MHz; MeOD): δ 6.84 (dd, 1H), 7.59 (m, 2H), 7.79 (s,1H), 8.08 (bs, 1H).

b)(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile

The title compound was prepared from2-chloro-3-fluoro-4-(1H-pyrazol-5-yl)benzonitrile (0.075 g, 0.34 mmol)and (S)-tert-butyl (1-hydroxypropan-2-yl)-carbamate (0.059 g, 0.34 mmol)using the method of Example 34(c) to afford 0.051 g of the titleproduct. ¹H NMR (400 MHz; CDCl₃): δ 1.15 (d, 3H), 1.34 (bs, 2H), 3.49(m, 1H), 3.95 (dd, 1H), 4.16 (dd, 1H), 6.79 (dd, 1H), 7.48 (m, 1H), 7.52(d, 1H), 8.07 (m, 1H).

c)(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile(0.05 g, 0.18 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (0.028 g,0.18 mmol) using DMF (3 mL) as solvent using the method of Example34(d). Yield 0.056 g. ¹H NMR (400 MHz; CDCl₃): δ 1.16 (d, 3H), 2.46 (s,3H), 4.29 (m, 2H), 4.49 (m, 1H), 6.70 (dd, 1H), 7.17 (bs, 1H), 7.50 (m,2H), 8.06 (m, 1H).

Example 228(S)-3-acetyl-N-(1-(3-(3,5-dichloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamidea) 4-bromo-3,5-dichloroaniline

3,5-Dichloroaniline (10 g, 61.7 mmol) in acetonitrile (100 mL) was takenin a 3-necked flask fitted with a thermometer, condenser and a droppingfunnel containing N-bromosuccinimide (10.99 g, 61.7 mmol) inacetonitrile (30 mL). N-bromosuccinimide solution was added slowly tothe 3,5-dichloroaniline solution in the flask at 0° C. by maintainingthe internal temperature below 5° C. After the addition of NBS, thereaction mixture was warmed to RT and stirred for further 3 h. After thecompletion of the reaction as evidenced by LC-MS, the mixture wasdiluted with 10% aq. NaHSO₃ (150 mL). The solution was stirred for 15min and evaporated to ⅓ of the total volume of the solvents. Theresultant mixture was then diluted with water and extracted with ethylacetate. The organic solvent was dried, evaporated and purified byCombiFlash to give pure 4-bromo-3,5-dichloroaniline. Yield 13.6 g. ¹HNMR (400 MHz; d₆-DMSO): δ 5.82 (bs, 2H), 6.75 (s, 2H).

b) 4-amino-2,6-dichlorobenzonitrile

The title compound was prepared from the reaction of4-bromo-3,5-dichloroaniline (6.88 g, 28.6 mmol) and Copper(I)cyanide(2.56 g, 28.6 mmol) in DMF (48 mL) under microwave irradiation at 190°C. for 1 h. After the completion of the reaction, the mixture was cooledto RT and quenched with 200 mL of 12% ammonia solution. The resultantmixture was stirred for 30 min at RT and the precipitate was filtered,washed with water and dried under vacuum. Yield 3.725 g. ¹H NMR (400MHz; d₆-DMSO): δ 6.70 (s, 1H), 6.79 (s, 1H).

c) 2,6-dichloro-4-iodobenzonitrile

4-amino-2,6-dichlorobenzonitrile (1.65 g, 8.82 mmol) was stirred in 7.5mL of 12M HCl solution. The reaction mixture was cooled with ice-bath.Sodium nitrite (0.6 g, 8.82 mmol) dissolved in 6 mL of water was addeddrop-wise to the flask under cold condition, followed by the drop-wiseaddition of cold potassium iodide (5.86 g, 35.3 mmol) solution in water(12 mL). The mixture was allowed to stir at RT for a day. After thecompletion of the reaction, the mixture was extracted with ethylacetate, washed with 10% Na₂SO₃ solution and brine. The organic layerwas dried over anhydrous Na₂SO₄ and evaporated. The solid obtained waswashed with heptane-ethyl acetate mixture (5:1) and dried under vacuum.Yield 1.09 g. ¹H NMR (400 MHz; d₆-DMSO): δ 6.71 (s, 1H), 6.81 (s, 1H).

d) 2,6-dichloro-4-(1H-pyrazol-5-yl)benzonitrile Hydrochloride

The title compound was prepared from 2,6-dichloro-4-iodobenzonitrile(1.09 g, 3.66 mmol) and1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester(1.32 g, 4.76 mmol) as described in Example 34 (a) and (b) until theisolation of the hydrochloride. Yield 0.824 g. ¹H NMR (400 MHz;d₆-DMSO): δ 7.07 (d, 1H), 7.88 (d, 1H), 8.14 (s, 2H).

e) (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-dichlorobenzonitrile

The title compound was prepared from 2,6-dichloro-4-(1H-pyrazol-5-yl)benzonitrile (0.75 g, 3.15 mmol) and(S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (0.552 g, 3.15 mmol)using the method of Example 34(c). Yield 0.121 g. ¹H NMR (400 MHz;CDCl₃): δ 1.15 (d, 3H), 1.54 (bs, 2H), 3.49 (m, 1H), 3.93 (dd, 1H), 4.14(dd, 1H), 6.60 (d, 1H), 7.50 (d, 1H), 7.84 (s, 2H).

f)(S)-3-Acetyl-N-(1-(3-(3,5-dichloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-dichlorobenzonitrile(0.121 g, 0.41 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.063 g,0.41 mmol), HOBt (0.083 g, 0.615 mmol), DIPEA (0.214 mL, 1.23 mmol) andEDCI (0.118 g, 0.615 mmol) using DMF (10 mL) as solvent using the methodof Example 34(d). Yield 6.3 mg. ¹H NMR (400 MHz; CDCl₃): δ 1.29 (d, 3H),2.55 (s, 3H), 4.36 (m, 2H), 4.57 (m, 1H), 6.64 (d, 1H), 7.40 (s, 1H),7.58 (d, 1H), 7.83 (s, 2H).

Example 229N—((S)-1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide of Example 227 (0.05 g, 0.122mmol) was reacted with sodium borohydride (0.009 g, 0.244 mmol) usingthe method of Example 84. Yield of the title compound 0.015 g. ¹H NMR(400 MHz; MeOD): δ 1.23 (d, 3H), 1.49 (d, 3H), 4.39 (m, 2H), 4.55 (m,1H), 6.56 (s, 1H), 6.77 (dd, 1H), 7.67 (d, 1H), 7.75 (d, 1H), 8.17 (m,1H).

Example 230(S)—N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-isopropyl-1,2,4-oxadiazole-5-carboxamidea) 3-isopropyl-1,2,4-oxadiazole-5-carboxylic Acid

The title compound was prepared from ethyl3-isopropyl-1,2,4-oxadiazole-5-carboxylate (0.4 g, 2.17 mmol) and sodiumhydroxide solution (6 mL) using the method of Example 225(b). Yield 0.25g. ¹H NMR (400 MHz; D₂O): δ 1.33 (d, 6H), 3.17 (m, 1H).

b)(S)—N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-isopropyl-1,2,4-oxadiazole-5-carboxamide

The title compound was synthesized from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile(0.168 g, 0.64 mmol), 3-isopropyl-1,2,4-oxadiazole-5-carboxylic acid(0.1 g, 0.64 mmol), HOBt (0.13 g, 0.96 mmol), DIPEA (0.335 mL, 1.92mmol) and EDCI (0.184 g, 0.96 mmol) using DMF as solvent using themethod of Example 34(d). Yield of the title compound 5 mg. ¹H NMR (400MHz; MeOD): δ 1.27 (d, 3H), 1.36 (d, 6H), 3.16 (m, 1H), 4.39 (m, 2H),4.58 (m, 1H), 6.80 (d, 1H), 7.62 (m, 2H), 7.72 (d, 1H).

Example 231N—((R)-2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-5-(1-hydroxyethyl)isoxazole-3-carboxamide

(R)-5-acetyl-N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)isoxazole-3-carboxamide (0.047 g, 0.136 mmol) of Example 226 was reactedwith sodium borohydride (0.010 g, 0.272 mmol) using the method describedin Example 84. Yield of the title compound 0.045 g. ¹H NMR (400 MHz;MeOD): δ 1.50 (dd, 3H), 1.59 (d, 3H), 3.75 (m, 2H), 4.93 (m, 1H), 6.53(m, 1H), 6.79 (d, 1H), 7.67 (m, 2H), 7.73 (d, 1H).

Example 232N—((R)-1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)isoxazole-3-carboxamidea)(R)-5-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide

The title compound was prepared from(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile(0.214 g, 0.81 mmol) and 5-acetylisoxazole-3-carboxylic acid (0.127 g,0.81 mmol) using the method of Example 34(d). Yield 0.166 g. ¹H NMR (400MHz; MeOD): δ 1.28 (d, 3H), 2.59 (s, 3H), 4.37 (m, 2H), 4.60 (m, 1H),6.80 (d, 1H), 7.27 (s, 1H), 7.64 (m, 2H), 7.72 (d, 1H).

b)N—((R)-1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)isoxazole-3-carboxamide

Following the method described in Example 84, the starting materials(R)-5-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide(0.147 g, 0.4 mmol) and sodium borohydride (0.03 g, 0.8 mmol) afforded0.135 g of the title product. ¹H NMR (400 MHz; MeOD): δ 1.26 (d, 3H),1.51 (dd, 3H), 4.36 (m, 2H), 4.57 (m, 1H), 4.94 (m, 1H), 6.52 (m, 1H),6.79 (d, 1H), 7.65 (m, 2H), 7.71 (d, 1H).

Example 233(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide

The title compound was obtained from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile(0.4 g, 1.43 mmol), 5-acetylisoxazole-3-carboxylic acid (0.223 g, 1.43mmol), HOBt (0.291 g, 2.15 mmol), DIPEA (0.75 mL, 4.31 mmol) and EDCI(0.413 g, 2.15 mmol) using DMF (10 mL) as solvent using the method ofExample 34(d). Yield 47 mg. LC-MS: m/z [M+H⁺] calculated forC₁₉H₁₅ClFN₅O₃ ⁺: 415.8; found: 415.9.

Example 234N—((S)-1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)isoxazole-3-carboxamide

(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide (0.04 g, 0.096 mmol) of Example 233was reacted with sodium borohydride (0.007 g, 0.192 mmol) using themethod of Example 84. Yield of the title compound 0.023 g. ¹H NMR (400MHz; MeOD): δ 1.26 (d, 3H), 1.51 (dd, 3H), 4.38 (m, 2H), 4.59 (m, 1H),4.94 (m, 1H), 6.52 (m, 1H), 6.77 (dd, 1H), 7.63 (m, 1H), 7.74 (m, 1H),8.12 (m, 1H).

Example 236(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(morpholinomethyl)-1H-pyrazole-5-carboxamidea) Ethyl 3-(morpholinomethyl)-1H-pyrazole-5-carboxylate

The title compound was prepared from 1-morpholinopropan-2-one (4.192 g,29.3 mmol), Sodium (0.43 g, 29.3 mmol), diethyl oxalate (4.28 g, 29.3mmol) and hydrazine hydrochloride (2 g, 29.3 mmol) using the method ofExample 225(a). Yield 18%. ¹H NMR (400 MHz; CDCl₃): δ 1.39 (t, 3H), 2.48(m, 4H), 3.60 (d, 2H), 3.71 (m, 4H), 4.38 (q, 2H), 6.74 (s, 1H).

b) 3-(morpholinomethyl)-1H-pyrazole-5-carboxylic Acid

The title compound was prepared from ethyl3-(morpholinomethyl)-1H-pyrazole-5-carboxylate (0.138 g, 0.57 mmol) andsodium hydroxide solution (2 mL) using the method of Example 225(b).Yield 0.119 g. ¹H NMR (400 MHz; MeOD): δ 3.22 (m, 2H), 3.46 (m, 2H),3.78 (m, 2H), 4.05 (m, 2H), 4.43 (s, 2H), 7.05 (s, 1H).

c)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(morpholinomethyl)-1H-pyrazole-5-carboxamide

The title compound was synthesized from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.147 g,0.56 mmol), 3-(morpholinomethyl)-1H-pyrazole-5-carboxylic acid (0.119 g,0.56 mmol), HOBt (0.114, 0.84 mmol), DIPEA (0.29 mL, 1.69 mmol) and EDCI(0.162 g, 0.84 mmol) using DMF (10 mL) as solvent using the method ofExample 34(d). Yield 0.256 g. ¹H NMR (400 MHz; MeOD): δ 1.24 (d, 3H),2.44 (m, 4H), 3.59 (s, 2H), 3.67 (m, 4H), 4.35 (m, 2H), 4.55 (m, 1H),6.62 (bs, 1H), 6.74 (d, 1H), 7.69 (d, 1H), 7.76 (d, 1H), 7.88 (m, 1H),8.00 (m, 1H).

Example 236(S)—N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(morpholinomethyl)isoxazole-3-carboxamidea) Ethyl 5-(morpholinomethyl)isoxazole-3-carboxylate

To the solution of ethyl chlorooximidoacetate (0.588 g, 3.88 mmol) and4-(prop-2-ynyl)morpholine (0.971 g, 7.76 mmol) in toluene (5 mL) wasadded solution of triethylamine (0.54 mL, 3.88 mmol) in toluene (5 mL)dropwise. The resultant mixture was stirred at RT for 5 h. After thecompletion of the reaction as evidenced by LC-MS, the reaction mixturewas diluted with water and extracted with ethyl acetate. The organicsolvent was then dried over anhydrous sodium sulfate and evaporated. Thecrude product was purified by Combiflash (Heptane:EtOAc eluent). Yield0.2 g. ¹H NMR (400 MHz; MeOD): δ 1.38 (t, 3H), 2.53 (m, 4H), 3.69 (m,4H), 3.78 (d, 2H), 4.41 (q, 2H), 6.73 (m, 1H).

b) 5-(morpholinomethyl)isoxazole-3-carboxylic Acid

The title compound was prepared from ethyl5-(morpholinomethyl)isoxazole-3-carboxylate (0.2 g, 0.85 mmol) andsodium hydroxide solution (2 mL) using the method of Example 225(b).Yield 0.25 g. ¹H NMR (400 MHz; D₂O): δ 3.46 (m, 4H), 3.99 (m, 4H), 4.72(s, 2H), 7.10 (m, 1H).

c)(S)—N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(morpholinomethyl)isoxazole-3-carboxamide

The title compound was synthesized from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile(0.2 g, 0.72 mmol), 5-(morpholinomethyl)-isoxazole-3-carboxylic acid(0.15 g, 0.72 mmol), HOBt (0.145 g, 1.07 mmol), DIPEA (0.37 mL, 2.15mmol) and EDCI (0.2 g, 1.07 mmol) using DMF (10 mL) as the solvent usingthe method of Example 34(d). Yield 72 mg. ¹H NMR (400 MHz; d₆-DMSO): δ1.17 (d, 3H), 2.39 (m, 4H), 3.56 (m, 4H), 3.71 (s, 2H), 4.34 (m, 2H),4.46 (m, 1H), 6.62 (s, 1H), 6.76 (m, 1H), 7.83 (m, 1H), 7.88 (d, 1H),8.03 (m, 1H).

Example 237(S)—N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxamidea) 3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylic Acid

Following the procedure described in U.S. Pat. No. 5,578,550 for thepreparation of ethyl 3-isopropyl-1,2,4-oxadiazole-5-carboxylate, thetitle product was prepared from (E)-N′-hydroxynicotinimidamide (2.727 g,19.88 mmol) and ethyl oxalyl chloride (2.89 mL, 25.9 mmol) followed bysubsequent ester hydrolysis with sodium hydroxide solution according toExample 225(b). Yield 1.32 g. ¹H NMR (400 MHz; d₆-DMSO): δ 7.63 (m, 1H),8.32 (m, 1H), 8.86 (dd, 1H), 9.03 (dd, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxamide

The title compound was synthesized from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile(0.2 g, 0.72 mmol), 3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylic acid(0.137 g, 0.72 mmol), HOBt (0.145 g, 1.07 mmol), DIPEA (0.375 mL, 2.15mmol) and EDCI (0.2 g, 1.07 mmol) using DMF as solvent using the methodof Example 34(d). Yield 33.4 mg. ¹H NMR (400 MHz; d₆-DMSO): δ 1.23 (d,3H), 4.41 (m, 2H), 4.52 (m, 1H), 6.79 (m, 1H), 7.65 (m, 1H), 7.78 (m,1H), 7.95 (d, 1H), 8.03 (m, 1H), 8.38 (m, 1H), 8.83 (dd, 1H), 9.19 (dd,1H), 9.51 (m, 1H).

Example 238(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxamide

Following the method of Example 34(d), the title compound was preparedfrom (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(0.27 g, 1.05 mmol), 3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylic acid(0.2 g, 1.05 mmol), HOBt (0.21 g, 1.57 mmol), DIPEA (0.55 mL, 3.14 mmol)and EDCI (0.3 g, 1.57 mmol) using DMF as solvent to afford 54 mg of thetitle product. ¹H NMR (400 MHz; d₆-DMSO): δ 1.23 (d, 3H), 4.37 (m, 2H),4.50 (m, 1H), 6.96 (d, 1H), 7.65 (m, 1H), 7.88 (d, 1H), 7.92 (m, 2H),8.04 (m, 1H), 8.38 (m, 1H), 8.83 (dd, 1H), 9.19 (dd, 1H), 9.50 (m, 1H).

Example 239(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-imidazo[2,1-b]thiazole-6-carboxamidea) Ethyl imidazo[2,1-b]thiazole-6-carboxylate

To the cold solution of 2-aminothiazole (0.5 g, 4.99 mmol) in 10 mL ofDME was added ethyl bromopyruvate (0.783 mL, 6.24 mmol). The resultantmixture was stirred at RT for 30 min. The yellow precipitate obtainedwas filtered. The solid residue was dissolved in 20 mL of ethanol andrefluxed for 8 h. After the completion of the reaction as evidenced byLC-MS, the solvent was removed under vacuum. Residue was added to DCMand washed with sodium bicarbonate solution. The organic solvent wasevaporated and the crude product was purified by Combiflash. Yield 0.285g. ¹H NMR (400 MHz; CDCl₃): δ 1.42 (t, 3H), 4.41 (q, 2H), 6.98 (d, 1H),7.47 (d, 1H), 8.09 (s, 1H).

b) Imidazo[2,1-b]thiazole-6-carboxylic Acid

Following the method of Example 225(b), the title compound was obtainedfrom 0.285 g of ethyl imidazo[2,1-b]thiazole-6-carboxylate and 2 mL ofsodium hydroxide solution. Yield 0.379 g. ¹H NMR (400 MHz; D₂O): δ 7.53(d, 1H), 7.98 (d, 1H), 8.31 (s, 1H).

c) (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)imidazo[2,1-b]thiazole-6-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.31 g,1.19 mmol), imidazo[2,1-b]thiazole-6-carboxylic acid (0.2 g, 1.19 mmol),HOBt (0.24 g, 1.78 mmol), DIPEA (0.62 mL, 3.57 mmol) and EDCI (0.34 g,1.78 mmol) using DMF (10 mL) as solvent using the method of Example34(d) affording 232 mg of the product. ¹H NMR (400 MHz; MeOD): δ 1.24(d, 3H), 4.38 (m, 2H), 4.55 (m, 1H), 6.76 (d, 1H), 7.21 (d, 1H), 7.75(m, 3H), 7.90 (dd, 1H), 8.06 (m, 1H), 8.09 (s, 1H).

Example 240(S)—N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)imidazo[1,2-a]pyrimidine-2-carboxamide

The title compound was prepared using the method of Example 34(d) from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile(0.3 g, 1.07 mmol), imidazo[1,2-a]pyrimidine-2-carboxylic acid (0.17 g,1.07 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) andEDCI (0.31 g, 1.61 mmol) using DMF (10 mL) as solvent. Yield 0.29 g. ¹HNMR (400 MHz; CDCl₃): δ 1.25 (d, 3H), 4.30 (dd, 1H), 4.49 (dd, 1H), 4.65(m, 1H), 6.81 (dd, 1H), 6.98 (dd, 1H), 7.53 (d, 1H), 7.73 (dd, 1H), 8.08(s, 1H), 8.48 (dd, 1H), 8.67 (m, 3H).

Example 241(S)—N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)imidazo[1,2-a]pyrazine-2-carboxamide

Following the method described in Example 34(d), the title compound wasprepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile(0.34 g, 1.22 mmol), imidazo[1,2-a]pyrazine-2-carboxylic acid (0.2 g,1.22 mmol), HOBt (0.25 g, 1.84 mmol), DIPEA (0.64 mL, 3.68 mmol) andEDCI (0.35 g, 1.84 mmol) using 10 mL of DMF as solvent. Yield 0.26 g. ¹HNMR (400 MHz; MeOD): δ 1.30 (d, 3H), 4.44 (m, 2H), 4.58 (m, 1H), 6.77(dd, 1H), 7.59 (dd, 1H), 7.78 (d, 1H), 7.90 (d, 1H), 8.14 (dd, 1H), 8.36(d, 1H), 8.49 (dd, 1H), 9.06 (bs, 1H).

Example 242(S)—N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-isopropyl-1,2,4-oxadiazole-5-carboxamide

The title compound was obtained from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile(0.36 g, 1.28 mmol), 3-isopropyl-1,2,4-oxadiazole-5-carboxylic acid (0.2g, 1.28 mmol), HOBt (0.26 g, 1.92 mmol), DIPEA (0.67 mL, 3.84 mmol) andEDCI (0.37 g, 1.92 mmol) using DMF (10 mL) as solvent using the methodof Example 34(d). Yield 0.144 g. ¹H NMR (400 MHz; MeOD): δ 1.29 (d, 3H),1.34 (d, 6H), 3.15 (m, 1H), 4.41 (m, 2H), 4.58 (m, 1H), 6.79 (dd, 1H),7.62 (dd, 1H), 7.76 (d, 1H), 8.08 (dd, 1H).

Example 243(S)—N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1H-imidazol-4-yl)thiazole-4-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile(0.3 g, 1.07 mmol), 2-(1H-imidazol-4-yl)thiazole-4-carboxylic acid (0.25g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) andEDCI (0.31 g, 1.61 mmol) in 10 mL DMF as solvent using the methoddescribed in Example 34(d). Yield 65 mg. ¹H NMR (400 MHz; CDCl₃): δ 1.27(d, 3H), 4.40 (m, 2H), 4.60 (m, 1H), 6.80 (dd, 1H), 7.24 (d, 1H), 7.30(m, 1H), 7.56 (m, 2H), 7.70 (d, 1H), 8.02 (s, 1H), 8.08 (m, 1H).

Example 244(S)—N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(morpholinomethyl)thiazole-4-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile(0.3 g, 1.07 mmol), 2-(morpholinomethyl)thiazole-4-carboxylic acid (0.29g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) andEDCI (0.31 g, 1.61 mmol) in 10 mL DMF as solvent using the method ofExample 34(d). Yield 0.27 g. ¹H NMR (400 MHz; d₆-DMSO): δ 1.13 (d, 3H),3.61 (m, 4H), 3.84 (d, 2H), 4.39 (m, 3H), 6.78 (dd, 1H), 7.84 (dd, 1H),7.90 (d, 1H), 8.06 (dd, 1H), 8.15 (s, 1H), 8.45 (d, 1H).

Example 246N—((S)-1-(3-(3,5-dichloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

The title compound was prepared from(S)-3-acetyl-N-(1-(3-(3,5-dichloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide(63 mg, 0.15 mmol) and sodium borohydride (11 mg, 0.29 mmol) using themethod of Example 84. Yield 15 mg. ¹H NMR (400 MHz; CDCl₃): δ 1.23 (d,3H), 1.54 (d, 3H), 4.34 (m, 2H), 4.54 (m, 1H), 4.96 (q, 1H), 6.61 (m,2H), 7.52 (d, 1H), 7.90 (m, 2H).

Example 246(S)—N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile(0.3 g, 1.07 mmol), 5-(2-hydroxypropan-2-yl)-isoxazole-3-carboxylic acid(0.22 g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23mmol) and EDCI (0.31 g, 1.61 mmol) using DMF (10 mL) as solvent usingthe method of Example 34(d). Yield 40 mg. 1H NMR (400 MHz; CDCl₃): δ1.23 (d, 3H), 1.62 (s, 6H), 4.36 (m, 2H), 4.59 (m, 1H), 6.57 (m, 1H),6.82 (dd, 1H), 7.54 (m, 2H), 8.00 (m, 1H), 8.20 (m, 1H).

Example 247(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide

4-Imidazolecarboxylic acid (1.00 g, 8.9 mmol) was dissolved in dry DMF(35 ml). Dry 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDCI, 2.31 g, 12.0 mmol), HOBt (1.84 g, 12.0 mmol), and DIPEA (4.7 ml,3.46 g, 26.8 mmol) were added at RT. After stirring for 15 min(S)-4-[1-(2-aminopropyl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile ofExample 340 (2.44 g, 9.4 mmol) in dry DMF (15 ml) was added to thesolution at RT. Then the solution was stirred for 45 h. Water was addedand the product was extracted into ethyl acetate. The organic phase waswashed with brine and water, dried and evaporated. The crude product waspurified by triturating in hot DCM. The product was filtered and washedwith heptane. ¹H NMR (400 MHz, DMSO-d₆): 1.08 (3H, d), 4.30 (1H,distorted dd), 4.41 (2H, m), 6.95 (1H, d), 7.57 (1H, s), 7.75 (1H, d),7.85 (1H, d), 8.01 (2H, m), 8.21 (1H, s), 8.30 (1H, d), 12.47 (1H, broads).

Example 248(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide

2-Methyl-1H-imidazole-4-carboxylic acid (1.364 g, 10.82 mmol) wassuspended in N,N-Dimethyl formamide (25 ml).O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(0.342 g, 0.901 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.073 g, 10.82 mmol), DIPEA (3.14 ml, 18.03 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (2.5 g,9.01 mmol) were rapidly added into the mixture, respectively. Thereaction mixture was stirred at RT overnight. Next day water was slowlyadded and the mixture was extracted twice with DCM. The combined organicphases were extracted three times with water and the DCM-layer wasevaporated. The product was crystallized from acetonitrile/water mixtureand finally dried with vacuum at 40° C. Yield 71.6%. ¹H-NMR (400 MHz;d6-DMSO): δ 1.08 (d, 3H), 2.31 (s, 3H), 4.27 (dd, 1H), 4.32-4.48 (m,2H), 6.95 (d, 1H), 7.41 (s, 1H), 7.82 (d, 1H), 7.95-8.02 (m, 2H), 8.04(d, 1H), 8.10 (m, 1H), 12.10 (bs, 1H).

Example 249(S)—N-{1-[3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide

The title compound was prepared according to the method of Example 247starting from 2-methyl-1H-imidazole-4-carboxylic acid and(S)-4-[1-(2-aminopropyl)-1H-pyrazol-3-yl]-2-chloro-6-fluorobenzonitrile(which can be prepared according to Example 34(c)). The crude productwas purified by flash chromatography on silica gel by using CH₂Cl₂-MeOHas a gradient eluent (100:0-98:2) to give the product, which wastriturated in diethyl ether at RT to afford the title compound. ¹H NMR(400 MHz, DMSO-d₆): 1.06 (3H, d), 2.31 (3H, s), 4.28 (1H, distorted dd),4.35-4.45 (2H, m), 7.02 (1H, d), 7.42 (1H, s), 7.86 (1H, d), 7.93 (1H,dd), 8.00 (1H, d), 8.07 (1H, d), 12.11 (1H, s).

Example 250(S)—N-{2-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propyl}-2-methyl-1H-imidazole-4-carboxamide

The title compound was prepared using the method of Example 247 startingfrom 2-methyl-1H-imidazole-4-carboxylic acid and(S)-4-[1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile. Thecrude product was purified by triturating in DCM at RT. ¹H NMR (400 MHz,DMSO-d₆): 1.44 (3H, d), 2.27 (3H, s), 3.57 (1H, m), 3.67 (1H, m), 4.68(1H, m), 6.96 (1H, d), 7.44 (1H, s), 7.89 (1H, d), 7.95-7.99 (3H, m),8.12 (1H, s), 12.1 (1H, broad s).

Example 251(R)—N-{2-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propyl}-2-methyl-1H-imidazole-4-carboxamidea) (R)-tert-Butyl 2-hydroxypropylcarbamate

Di-tert-butyl dicarbonate (10.17 g, 46.6 mmol) in DCM (30 ml) was addedslowly to a solution of (R)-(−)-1-amino-2-propanol (3.67 ml, 46.6 mmol)in DCM (60 ml). After addition stirring was continued at RT overnight.The reaction mixture was then diluted with DCM (200 ml) and washed withwater (2×100 ml). The organic layer was dried, filtered and evaporatedto give the title compound. ¹H NMR (400 MHz, CDCl₃): 1.18 (3H, d), 1.45(9H, s), 2.47 (1H, broad s), 3.00 (1H, m), 3.26 (1H, m), 3.90 (1H, m),4.96 (1H, broad s)

b) (R)-4-[1-(1-Aminopropan-2-yl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile

(R)-4-[1-(1-Aminopropan-2-yl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile wasprepared using the method of Example 34(c) starting from2-chloro-4-(1H-pyrazol-3-yl)benzonitrile and (R)-tert-butyl2-hydroxypropylcarbamate. ¹H NMR (400 MHz, CDCl₃): 1.24 (2H, broad s),1.54 (3H, d), 3.05 (1H, distorted dd), 3.17 (1H, distorted dd), 4.34(1H, m), 6.61 (1H, d), 7.52 (1H, d), 7.66 (1H, d), 7.78 (1H, dd), 7.98(1H, d).

c)(R)—N-{2-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propyl}-2-methyl-1H-imidazole-4-carboxamide

(R)—N-{2-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propyl}-2-methyl-1H-imidazole-4-carboxamidewas prepared using the method of Example 247 starting from2-methyl-1H-imidazole-4-carboxylic acid and(R)-4-[1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile. Thecrude product was purified by flash chromatography on silica gel byusing CH₂Cl₂-MeOH (98:2) as an eluent. The resulting product wastriturated in DCM at RT to afford the title compound. ¹H NMR (400 MHz,CDCl₃): 1.61 (3H, d), 2.39 (3H, s), 3.74-3.81 (1H, m), 3.85-3.91 (1H,m), 4.63 (1H, m), 6.59 (1H, d), 7.45 (1H, d), 7.49 (1H, d), 7.62 (1H,t), 7.66 (1H, d), 7.84 (1H, dd), 8.00 (1H, d), 10.04 (1H, broad s).

Example 252(S)—N-{1-[3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-methyl-1H-imidazole-4-carboxamide

The title compound was prepared using the method of Example 247 startingfrom 1-methyl-1H-imidazole-4-carboxylic acid and(S)-4-[1-(2-aminopropyl)-1H-pyrazol-3-yl]-2-chloro-6-fluorobenzonitrile(which can be prepared according to Example 34(c)). The crude productwas purified by flash chromatography on silica gel by using CH₂Cl₂-MeOHas a gradient eluent (100:0-99:1). The resulting product was trituratedin diethyl ether at RT to afford the title product. ¹H NMR (400 MHz,DMSO-d₆): 1.21 (3H, d), 3.74 (3H, s), 4.26 (1H, distorted dd), 4.42 (1H,distorted dd), 4.56 (1H, m), 6.60 (1H, d), 7.43 (1H, d), 7.49 (1H, d),7.50 (1H, d), 7.75 (1H, dd), 7.87 (1H, m), 7.97 (1H, d).

Example 253(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-ethyl-1H-imidazole-4-carboxamide

(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide(250 mg, 0.705 mmol) in dry DMF (3 ml) was added slowly to the mixtureof dry DMF (1 ml) and 55% NaH (61.4 mg, 1.41 mmol) at 0° C. under annitrogen atmosphere. Thereafter the reaction mixture was stirred at RTfor 30 min. The reaction mixture was recooled to 0° C. Iodoethane (0.057ml, 0.712 mmol) was slowly added at 0° C. and then the reaction mixturewas stirred at RT overnight. The reaction mixture was quenched withbrine (20 ml), pH was adjusted over 9 with NaOH and the product wasextracted into ethyl acetate (3×30 ml). The combined organic layers werewashed with water, dried and concentrated. Flash chromatography onsilica gel by using CH₂Cl₂-MeOH as a gradient eluent (100:0-99:1)afforded the title product. ¹H NMR (400 MHz, DMSO-d₆): 1.07 (3H, d),1.34 (3H, t), 4.02 (2H, q), 4.20 (1H, distorted dd), 4.34 (2H, m), 6.95(1H, d), 7.67 (1H, d), 7.76 (1H, d), 7.84 (1H, d), 8.00 (2H, m), 8.20(1H, d), 8.27 (1H, d).

Example 254(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1,2-dimethyl-1H-imidazole-4-carboxamide

(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide(700 mg, 1.90 mmol), EtOH (22 ml), KOH (151 mg, 2.70 mmol) andiodomethane (0.26 ml, 593 mg, 4.18 mmol) were added to a microwave ovenreaction vial. The reaction mixture was stirred at RT for 74 h. Thenwater was added and the solution was evaporated to dryness. Water wasadded again and the precipitation was filtered and washed with water andheptane. Flash chromatography on silica gel by using CH₂Cl₂-MeOH as agradient eluent (100:0-99:1) afforded the product, which wasrecrystallized in ethyl acetate, filtered at RT and washed with heptanesto afford the title compound. ¹H NMR (400 MHz, CDCl₃): 1.22 (3H, d),2.39 (3H, s), 3.60 (3H, s), 4.29 (1H, distorted dd), 4.38 (1H, distorteddd), 4.55 (1H, m), 6.60 (1H, d), 7.41 (1H, s), 7.48 (1H, d), 7.54 (1H,d), 7.66 (1H, d), 7.85 (1H, dd), 7.99 (1H, d).

Example 255(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-isopropyl-2-methyl-1H-imidazole-4-carboxamide

(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-isopropyl-2-methyl-1H-imidazole-4-carboxamidewas prepared using the method of Example 253 starting from(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamideand 2-iodopropane. ¹H NMR (400 MHz, CDCl₃): 1.22 (3H, d), 1.43 (6H, d),2.42 (3H, s), 4.29 (2H, m), 4.39 (1H, distorted dd), 4.57 (1H, m), 6.61(1H, d), 7.49 (1H, d), 7.56 (1H, s), 7.59 (1H, d), 7.66 (1H, d), 7.86(1H, dd), 8.00 (1H, d).

Example 256(S)—N-{2-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propyl}-1-isopropyl-2-methyl-1H-imidazole-4-carboxamide

The title compound was prepared using the method of Example 253 startingfrom(S)—N-{2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propyl}-2-methyl-1H-imidazole-4-carboxamideand 2-iodopropane. ¹H NMR (400 MHz, CDCl₃): 1.42 (3H, d), 1.43 (3H, d),1.60 (3H, d), 2.37 (3H, s), 3.77 (1H, m), 3.88 (1H, m), 4.28 (1H, m),4.63 (1H, m), 6.58 (1H, d), 7.50 (1H, d), 7.51 (1H, t), 7.59 (1H, s),7.66 (1H, d), 7.84 (1H, dd), 8.00 (1H, d).

Example 257(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-oxobutyl)-1H-imidazole-4-carboxamide

(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide(600 mg, 1.69 mmol) and methyl vinyl ketone (0.42 ml, 5.18 mmol) wereadded to a solution of 1-methylimidazole (7 μl, 0.085 mmol) in DMSO (6ml). The reaction mixture was stirred at 70° C. for 11 h. Then water wasadded and the product was extracted into ethyl acetate. The combinedorganic layers were washed with water, dried and concentrated. The crudeproduct was purified by flash chromatography on silica gel by usingCH₂Cl₂-MeOH as a gradient eluent (100:0-98:2) to obtain the titlecompound. ¹H NMR (400 MHz, CDCl₃): 1.21 (3H, d), 2.16 (3H, s), 2.92 (2H,t), 4.26 (2H, t), 4.28 (1H, distorted dd), 4.39 (1H, distorted dd), 4.56(1H, m), 6.60 (1H, d), 7.48 (1H, d), 7.50 (1H, d), 7.52 (1H, d), 7.66(1H, distorted d), 7.79 (1H, distorted dd), 7.86 (1H, d), 8.17 (1H, d).

Example 258(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide

(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamidewas prepared using the method of the previous Example starting from(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamideand methyl vinyl ketone. ¹H NMR (400 MHz, CDCl₃): 1.21 (3H, d), 2.17(3H, s), 2.44 (3H, s), 2.89 (2H, t), 4.13 (2H, t), 4.29 (1H, distorteddd), 4.38 (1H, distorted dd), 4.55 (1H, m), 6.60 (1H, d), 7.44 (1H, s),7.48 (1H, d), 7.58 (1H, d), 7.66 (1H, distorted d), 7.85 (1H, distorteddd), 8.00 (1H, d).

Example 259(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-hydroxy-3-methylbutyl)-1H-imidazole-4-carboxamide

(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-oxobutyl)-1H-imidazole-4-carboxamide(100 mg, 1.18 mmol) in dry THF (3 ml) was added to 3.0 M methylmagnesiumbromide solution in ether (0.39 ml) at 30-40° C. Thereafter the reactionmixture was stirred at 45° C. for 3 h. The cooled reaction mixture waspoured into saturated NH₄Cl solution. Solvents were evaporated and theproduct was extracted into ethyl acetate. The combined organic layerswere washed with water, dried and concentrated. The crude product waspurified by flash chromatography on silica gel by using EtOAc-MeOH (9:1)as an eluent. The final purification was made by preparative HPLC toobtain the title compound. ¹H NMR (400 MHz, CDCl₃): 1.22 (3H, d), 1.30(6H, s), 1.97 (2H, m), 4.14 (2H, m), 4.28 (1H, distorted dd), 4.41 (1H,distorted dd), 4.56 (1H, m), 6.60 (1H, d), 7.48 (2H, m), 7.56 (1H, d),7.61 (1H, distorted d), 7.79 (1H, distorted dd), 7.86 (1H, d), 8.17 (1H,d).

Example 260(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-hydroxy-3-methylbutyl)-2-methyl-1H-imidazole-4-carboxamide

The title compound was prepared using the method of the previous Examplestarting from(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamideand methylmagnesium bromide. The crude product was purified by flashchromatography on silica gel by using CH₂Cl₂-MeOH as a gradient eluent(100:1-98:2). The final purification was made by preparative HPLC toobtain the title compound. ¹H NMR (400 MHz, CDCl₃): 1.22 (3H, d), 1.30(6H, s), 1.65 (1H, broad s), 1.88 (2H, m), 2.42 (3H, s), 4.02 (2H, m),4.30 (1H, distorted dd), 4.38 (1H, distorted dd), 4.55 (1H, m), 6.60(1H, d), 7.47 (1H, s), 7.50 (1H, d), 7.62 (1H, d), 7.65 (1H, d), 7.84(1H, dd), 7.99 (1H, d).

Example 261N—{(S)-1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-hydroxybutyl)-1H-imidazole-4-carboxamide

Sodium borohydride (9.8 mg, 0.26 mmol) was added to a solution of(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-oxobutyl)-1H-imidazole-4-carboxamide(100 mg, 0.24 mmol) in ethanol (3 ml) at RT. Thereafter the reactionmixture was stirred at RT for 3 h. Then water was added and the productwas extracted into ethyl acetate. The combined organic layers werewashed with water and dried. The solvent was evaporated to obtain thetitle compound. ¹H NMR (400 MHz, CDCl₃): 1.21 (3H, d), 1.22 (3H, d),1.89 (2H, m), 2.31 (1H, broad s), 3.73 (1H, m), 4.15 (2H, m), 4.28 (1H,distorted dd), 4.40 (1H, distorted dd), 4.56 (1H, m), 6.61 (1H, d), 7.51(2H, m), 7.60 (1H, d), 7.66 (1H, distorted d), 7.79 (1H, m), 7.95 (1H,d), 8.18 (1H, d).

Example 262N—{(S)-1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-hydroxybutyl)-2-methyl-1H-imidazole-4-carboxamide

The title compound was prepared using the method of the previous Examplestarting from(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide.¹H NMR (400 MHz, CDCl₃): 1.22 (6H, d), 1.81 (2H, m), 2.41 (1H, m), 2.45(1H, broad s), 3.74 (1H, m), 4.03 (2H, m), 4.30 (1H, distorted dd), 4.38(1H, distorted dd), 4.55 (1H, m), 6.60 (1H, d), 7.51 (1H, d), 7.53 (1H,s), 7.65 (1H, d), 7.66 (1H, d), 7.85 (1H, dd), 7.99 (1H, d).

Example 263N—{(S)-1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-[(2-methyloxiran-2-yl)methyl]-1H-imidazole-4-carboxamideand1-(3-chloro-2-hydroxy-2-methylpropyl)-N—{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide

A mixture of(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide(120 mg, 0.338 mmol), 2-(chloromethyl)-2-methyl-oxirane (2.88 g, 27.1mmol and Y(NO₃)₃×6 H₂O (3.6 mg, 0.0093 mmol) was stirred under MW at120° C. for 30 min. After evaporation of oxirane the residue waspurified by flash chromatography on silica gel using CH₂Cl₂-MeOH as agradient eluent (100:0-99:1) to obtainN—{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-[(2-methyloxiran-2-yl)methyl]-1H-imidazole-4-carboxamideas a major product and1-(3-chloro-2-hydroxy-2-methylpropyl)-N—{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamideas a minor product.

N—{(S)-1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-[(2-methyloxiran-2-yl)methyl]-1H-imidazole-4-carboxamide:¹H NMR (400 MHz, CDCl₃): 1.22 (3H, d), 1.31 (3H, s), 2.58 and 2.77 (twodiasteromers, 1H, d), 4.08 and 4.35 (two diastereomers, 1H, distorteddd), 4.57 (1H, m), (1H, distorted dd), 6.62 (1H, d), 7.50 (1H, d), 7.51(1H, s), 7.59 (1H, d), 7.66 (1H, distorted d), 7.79 (1H, distorted dd),7.97 (1H, d), 8.20 (1H, d).

1-(3-Chloro-2-hydroxy-2-methylpropyl)-N—{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide:¹H NMR (400 MHz, CDCl₃): 1.20 (two diastereomers, 3H, m), 1.34 and 1.35(two diastereomers, 3H, s), 3.31-3.42 (two diasteromers, 2H, m),3.99-4.18 (two diastereomers, 2H, m), 4.21-4.43 (two diastereomers, 3H,m), 4.54 (1H, m), 6.61 (1H, d), 7.49 (1H, d), 7.57 (1H, s), 7.66 (1H,distorted d), 7.76 (1H, s), 7.78 (1H, m), 8.15 (1H, d), 8.20 (1H, d).

Example 264(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(pyridin-2-yl)-1H-imidazole-4-carboxamide

A microwave oven reaction tube was charged with CuI (5.5 mg, 0.028mmol), 1H-benzotriazole (6.7 mg, 0.056 mmol), DMSO (1 ml),2-bromopyridine (0.054 ml, 89 mg, 0.566 mmol),(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide(200 mg, 0.564 mmol) and KOt-Bu (89 mg, 0.789 mmol). The reactionmixture was stirred for 30 min at 150° C. in a microwave oven. Then themixture was cooled to RT, water was added and the product was extractedinto ethyl acetate. The combined organic layers were washed with waterand dried. After evaporation of the solvent the residue was purified byflash chromatography on silica gel using CH₂Cl₂-MeOH as a gradienteluent (100:0-99:1). Trituration in diethyl ether provided the desiredproduct. ¹H NMR (400 MHz, CDCl₃): 1.26 (3H, d), 4.29 (1H, distorted dd),4.45 (1H, distorted dd), 4.61 (1H, m), 6.62 (1H, d), 7.32 (1H, dd), 7.38(1H, d), 7.50 (1H, d), 7.66 (1H, d), 7.81 (1H, dd), 7.88 (1H, td), 8.00(1H, m), 8.18 (2H, m), 8.42 (1H, s), 8.53 (1H, d).

Example 265(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(pyridin-3-yl)-1H-imidazole-4-carboxamide

Under nitrogen atmosphere, a reaction flask was charged with K₂CO₃ (78mg, 0.564 mmol), CuI (10.7 mg, 0.056 mmol),1,3-di(2-pyridyl)-1,3-propanedione (12.8 mg, 0.056 mmol),(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide(200 mg, 0.564 mmol), dry DMF (4 ml) and 3-bromopyridine (0.054 ml, 89mg, 0.564 mmol). The reaction mixture was stirred for 4 h at 130° C.3-Bromopyridine (0.025 ml, 41 mg, 0.260 mmol) was added, and thenheating was continued for 2 h at 130° C. Then the reaction mixture wascooled to RT and passed through a plug of Celite. After being rinsedwith ethyl acetate, the combined filtrates were washed with saturatedbrine, dried and concentrated. The residue was purified by flashchromatography on silica gel using CH₂Cl₂-MeOH (98:2) as an eluent.Recrystallization in CH₂Cl₂-Et₂O provided the desired product. ¹H NMR(400 MHz, CDCl₃): 1.25 (3H, d), 4.29 (1H, distorted dd), 4.46 (1H,distorted dd), 4.62 (1H, m), 6.64 (1H, d), 7.50 (1H, m), 7.51 (1H, d),7.68 (1H, distorted d), 7.74 (1H, m), 7.80 (1H, distorted dd), 7.87 (1H,d), 7.91 (1H, d), 8.11 (1H, d), 8.24 (1H, d), 8.71 (1H, dd), 8.78 (1H,d).

Example 266(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1-(pyridin-3-yl)-1H-imidazole-4-carboxamide

Under nitrogen atmosphere, a reaction flask was charged with K₂CO₃ (94mg, 0.678 mmol), CuI (12.9 mg, 0.068 mmol),1,3-di(2-pyridyl)-1,3-propanedione (15.3 mg, 0.068 mmol),(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide(250 mg, 0.678 mmol), dry DMF (5 ml) and 3-bromopyridine (0.065 ml, 107mg, 0.678 mmol). The reaction mixture was stirred for 2 h at 130° C.3-Bromopyridine (0.070 ml, 115 mg, 0.727 mmol) was added, and thenheating was continued for 4 h at 140° C. 3-Bromopyridine (0.070 ml, 115mg, 0.727 mmol) was added again, and heating was continued for 1 h at170° C. under microwaves. Then the reaction mixture was cooled to RT andpassed through a plug of Celite. After being rinsed with ethyl acetate,the combined filtrates were washed with saturated brine, dried andconcentrated. The residue was purified by flash chromatography on silicagel using CH₂Cl₂-MeOH as a gradient eluent (99.5:0.5-98:2). ¹H NMR (400MHz, CDCl₃): 1.25 (3H, d), 2.40 (3H, s), 4.32 (1H, distorted dd), 4.43(1H, distorted dd), 4.61 (1H, m), 6.63 (1H, d), 7.50 (1H, m), 7.52 (1H,d), 7.64 (1H, s), 7.66 (1H, m), 7.67 (1H, d), 7.78 (1H, d), 7.87 (1H,dd), 8.03 (1H, d), 8.64 (1H, d), 8.74 (1H, dd).

Example 267(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}imidazo[1,2-a]pyridine-2-carboxamide

Following the method of Example 247 but substituting4-imidazolecarboxylic acid for imidazo[1,2-a]pyridine-2-carboxylic acid(described in WO 2005/030704), the title compound was obtained. Thecrude product was purified by flash chromatography using CH₂Cl₂-MeOH asa gradient eluent (100:0-99:1) and then by trituration in diethyl etherat RT. ¹H NMR (400 MHz, CDCl₃): 1.28 (3H, d), 4.33 (1H, distorted dd),4.45 (1H, distorted dd), 4.64 (1H, m), 6.61 (1H, d), 6.87 (1H, td), 7.28(1H, td), 7.51 (1H, d), 7.60 (1H, dd), 7.64 (1H, d), 7.84 (1H, dd), 8.02(1H, s), 8.04 (1H, d), 8.12 (1H, d), 8.15 (1H, dt).

Example 268(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide

Following the method of Example 247 but substituting4-imidazolecarboxylic acid for5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (prepared inWO 2007/108750 from imidazo[1,2-a]pyridine-2-carboxylic acid), the titlecompound was obtained. The crude product was purified by flashchromatography using CH₂Cl₂-MeOH (98:2) as an eluent. ¹H NMR (400 MHz,CDCl₃): 1.22 (3H, d), 1.94-2.04 (4H, m), 2.87 (2H, m), 3.99 (2H, t),4.30 (1H, distorted dd), 4.38 (1H, distorted dd), 4.55 (1H, m), 6.60(1H, d), 7.40 (1H, s), 7.48 (1H, d), 7.55 (1H, d), 7.66 (1H, d), 7.86(1H, dd), 7.99 (1H, d).

Example 269(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-3-isopropyl-1H-pyrazole-5-carboxamide

Following the method of Example 247 but substituting4-imidazolecarboxylic acid for 5-isopropyl-1H-pyrazole-3-carboxylic acid(prepared in WO 03/037432 A1), the title compound was obtained. Thecrude product was purified by flash chromatography using CH₂Cl₂-MeOH asa gradient eluent (100:0-98:2). ¹H NMR (400 MHz, CDCl₃): 1.22 (3H, d),1.30 (6H, d), 3.03 (1H, m), 4.27 (1H, distorted dd), 4.43 (1H, distorteddd), 4.58 (1H, m), 6.59 (1H, s), 6.61 (1H, d), 7.50 (1H, d), 7.67 (1H,distorted d), 7.76 (1H, distorted dd), 7.85 (1H, d), 8.19 (1H, d), 10.21(1H, broad s).

Example 270(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-3-vinyl-1H-pyrazole-5-carboxamide

Triethylamine (3.0 ml, 21.8 mmol) was added to a solution ofN—{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamideof Example 56 (1.74 g, 4.36 mmol) in DCM (40 ml) at 0° C. Thenmethanesulfonyl chloride (0.675 ml, 8.73 mmol) was added slowly at 0° C.After addition stirring was continued at RT overnight. The reactionmixture was then diluted with DCM and washed with 1 M HCl. The organiclayer was dried (Na₂SO₄), filtered and concentrated. Crystallization inDCM afforded the title compound. ¹H NMR (400 MHz, CDCl₃+a drop ofMeOH-d4): 1.25 (3H, d), 4.31 (1H, distorted dd), 4.39 (1H, distorteddd), 4.55 (1H, m), 5.38 (1H, d), 5.76 (1H, d), 6.60 (1H, dd), 6.63 (1H,d), 6.79 (1H, s), 7.55 (1H, d), 7.70 (1H, distorted d), 7.73 (1H, d),7.82 (1H, distorted dd), 7.96 (1H, d).

Example 271 3-Acetyl-N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)isoxazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide a)2-Chloro-4-formyl-3-methylbenzonitrile

A mixture of 2-chloro-4-iodo-3-methylbenzonitrile (150 g, 0.54 mol) andTHF (1200 ml) was cooled down to −32° C. A 2 M i-PrMgCl-THF-solution(541 ml, 1.08 mol) was added slowly during 1 h and the mixture wasstirred at −32° C. for 2 h. DMF (83 ml, 1.08 mol) was added at −32° C.and the reaction mixture was allowed to warm to RT. After stirringovernight 10% HCl solution (1000 ml) was added at 0° C. The layers wereseparated and the aqueous layer was extracted with diethyl ether (2×900ml). The combined organic layers were washed with saturated NaHCO₃solution (900 ml) and brine (750 ml). The organic layer was dried withNa₂CO₄, filtered and evaporated. The dried crude product (95 g) wastreated with hot n-heptane and activated carbon. The title compound wasobtained as a yellow solid and used without further purification. ¹H-NMR(400 MHz; CDCl₃): δ 2.78 (s, 3H), 7.71 (d, 1H), 7.84 (d, 1H), 10.36 (s,1H).

b) (E)-2-Chloro-4-((hydroxyimino) methyl)-3-methylbenzonitrile

2-chloro-4-formyl-3-methylbenzonitrile (5.0 g, 27.8 mmol) was dissolvedin dry THF (60 ml). Pyridine (6.7 ml, 84.0 mmol) and hydroxylaminehydrochloride (3.87 g, 55.7 mmol) were added to the solution. Themixture was heated to 70° C. and stirred for 4 h. THF was evaporated andice water (50 ml) was added. The mixture was stirred for 1 h and theprecipitate was filtered off and washed twice with cold water. Afterdrying (5.3 g) of the title compound was obtained. ¹H-NMR (400 MHz;d6-DMSO): δ 2.48 (s, 3H), 7.79 (m, 2H), 8.45 (s, 1H), 11.93 (s, 1H).

c) (Z)-3-Chloro-4-cyano-N-hydroxy-2-methylbenzimidoyl Chloride

(E)-2-chloro-4-((hydroxyimino) methyl)-3-methylbenzonitrile (0.64 g,3.27 mmol) was dissolved in DMF (20 ml) and cooled to 0° C.N-Chlorosuccinimide (0.48 g, 3.60 mmol) was added and the mixture wasallowed to warm at RT. The mixture was stirred overnight at RT andpoured into ice water (100 ml), extracted twice with EtOAc, The organicphase was washed with water and brine, dried over anhydrous Na₂SO₄,filtered and evaporated. The crude product (0.69 g) was used withoutpurification. ¹H-NMR (400 MHz; d6-DMSO): δ 2.42 (s, 3H), 7.64 (d, 1H),7.92 (d, 1H), 12.77 (s, 1H).

d) t-Butyl(2-(3-(3-chloro-4-cyano-2-methylphenyl)isoxazol-5-yl)ethyl)-carbamate

tert-Butyl but-3-yn-1-ylcarbamate (1.0 g, 4.37 mmol) was dissolved indry DCM (10 ml) and triethylamine (0.91 ml) was added at RT. Tert-butyl(2-(3-(3-chloro-4-cyano-2-methylphenyl)isoxazol-5-yl)ethyl)carbamate (1g, 4.37 mmol) in DCM (5 ml) was added to reaction mixture. After onehour in RT the reaction mixture was heated to reflux for 6 h. Water (30ml) was added and the aqueous phase was extracted with dichloromethaneand the combined organic phases were washed with water and brine anddried over anhydrous Na₂SO₄, filtered and evaporated. Crude product waspurified by Flash chromatography (Toluene-EtOAc 3/1) Product fractionswere combined and evaporated to give the title compound (0.71 g). ¹H-NMR(400 MHz; d6-DMSO): δ 1.36 (s, 9H), 2.48 (s, 3H), 2.95 (t, 2H), 3.32 (m,2H), 6.71 (s, 1H), 7.05 (bs, 1H), 7.63 (d, 1H), 7.95 (d, 1H).

e) 4-(5-(2-aminoethyl)isoxazol-3-yl)-2-chloro-3-methylbenzonitrile

tert-Butyl(2-(3-(3-chloro-4-cyano-2-methylphenyl)isoxazol-5-yl)ethyl)-carbamate(0.56 g, 1.55 mmol) was dissolved to DCM (20 ml). To this mixture wasadded TFA (1.15 ml) and stirred at RT overnight. The reaction mixturewas evaporated to dryness and dissolved to diethyl ether. 1 M HCl indiethyl ether solution was added and the mixture was stirred at RT for 2h. The HCl salt of the title compound (0.20 g) was filtered and dried.¹H-NMR (400 MHz; d6-DMSO): δ 2.50 (s, 3H), 2.92 (m, 2H), 3.22 (m, 2H),6.88 (s, 1H), 7.65 (d, 1H), 7.98 (d, 1H), 8.23 (bs, 3H).

f)3-acetyl-N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)isoxazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide

3-Acetyl-1H-pyrazole-5-carboxylic acid (31 mg; 0.203 mmol) and DIPEA(0.106 ml) were dissolved in 5 ml of dry DCM. HOBt hydrate (47 mg; 0.304mmol) and EDCI (58 mg; 0.304 mmol) were added at RT. 4-(5-(2-aminoethyl)isoxazol-3-yl)-2-chloro-3-methylbenzonitrile (53 mg; 0.203 mmol) wasadded and the reaction was stirred at RT for 4 h. DCM 10 ml of was addedand organic layer washed with 1M HCl, saturated NaHCO₃ and brine. Theorganic phase was dried over Na₂SO₄, filtered and evaporated to dryness.The crude product was triturated with n-heptane to give the titleproduct 32 mg. ¹H-NMR (400 MHz; d6-DMSO): δ 2.44 (s, 3H), 2.51 (s, 3H),3.12 (t, 2H), 3.63 (m, 2H), 6.75 (s, 1H), 7.30 (bs, 1H), 7.62 (d, 1H),7.94 (d, 1H), 8.73 (bs, 1H), 14.20 (s, 1H).

Example 272 N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)isoxazol-5-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide

N-(2-(3-(3-chloro-4-cyano-2-methylphenyl) isoxazol-5-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide was prepared from4-(5-(2-aminoethyl) isoxazol-3-yl)-2-chloro-3-methylbenzonitrilehydrochloride (54.8 g, 0.184 mmol),3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (34.8 mg, 0.184 mmol),HOBt hydrate (42.2 mg, 0.276 mmol), DIPEA (0.096 ml, 0.551 mmol) andEDCI (53 mg, 0.276 mmol) using DCM as solvent as described in previousExample. The crude product was purified by preparative HPLC to give thetitle compound 13 mg. ¹H-NMR (400 MHz; CDCl₃): δ 2.47 (s, 3H), 3.23 (t,2H), 3.89 (m, 2H), 6.30 (s, 1H), 7.09 (bs, 1H), 7.22 (bs, 1H), 7.40 (m,2H), 7.57 (d, 1H), 7.98 (d, 1H), 8.62 (bs, 1H), 8.95 (bs, 1H).

Example 273(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide

To a mixture of 1H-pyrazole-3-carboxylic acid (89 mg, 0.767 mmol) in DCM(5 ml), was added DIPEA (0.40 ml, 2.30 mmol).O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU, 291.0 mg, 0.767 mmol) at RT. The mixture was stirred for 15 minand solid (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(200 mg, 0.767 mmol) was added. The reaction was stirred overnight atRT. The solvent was evaporated and water was added. The pH of the waterphase was adjusted to 9-10 and the product was extracted to DCM. Theorganic layer was washed with water and brine, dried over Na₂SO₄ andevaporated. The crude product was purified with flash chromatography(DCM/EtOAc gradient) to give title compound 100 mg. ¹H-NMR (400 MHz;d6-DMSO): δ 1.11 (d, 3H), 4.36 (m, 3H), 6.58 (t, 1H), 6.93 (d, 1H), 7.79(m, 1H), 7.82 (d, 1H), 7.98 (d, 2H), 8.08 (bs, 1H), 8.25 (d, 1H), 13.20(s, 1H).

Example 274(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxamide

4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid (78 mg; 0.384mmol) and DIPEA (0.20 ml, 1.151 mmol) were dissolved in 5 ml of dry DMF.HOBt hydrate (88 mg; 0.575 mmol) and EDCI (110 mg; 0.575 mmol) wereadded at RT. Solid(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg;0.384 mmol) was added in one portion and the reaction was stirred for 2h at 60° C. temperature and stirred at RT overnight. Water (40 ml) wasadded and the mixture was allowed to stir 1 h at RT. The precipitatedproduct was filtered, dried in vacuum at 40° C. for 12 h, to give thetitle compound 136 mg. ¹H-NMR (400 MHz; d6-DMSO): δ 1.12 (d, 3H), 2.49(s, 3H), 4.40 (m, 3H), 6.97 (d, 1H), 7.48 (m, 1H), 7.88 (m, 2H), 8.02(m, 2H), 8.07 (d, 1H), 8.21 (m, 1H), 8.58 (m, 1H), 9.13 (d, 1H), 12.85(s, 1H).

Example 275(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(4-methylpyridin-3-yl)thiophene-2-carboxamidea) 5-(4-methylpyridin-3-yl) thiophene-2-carboxylic Acid

Ethyl 5-(4-methylpyridin-3-yl) thiophene-2-carboxylate (0.200 g, 0.809mmol) was dissolved in ethanol (5 ml). 2 M sodium hydroxide solution(0.809 ml, 1.617 mmol) was added and the mixture was stirred at RTovernight. Ethanol was evaporated and water (5 ml) was added. Theproduct was precipitated during the addition of 2 M HCl. The product wasfiltered and dried to give 98 mg. ¹H-NMR (400 MHz; d6-DMSO): δ 2.43 (s,3H), 7.38 (d, 1H), 7.39 (d, 1H), 7.77 (d, 1H), 8.46 (d, 1H), 8.59 (s,1H).

b) (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(4-methylpyridin-3-yl) thiophene-2-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.116 g,0.446 mmol), 5-(4-methylpyridin-3-yl)thiophene-2-carboxylic acid (0.098g, 0.446 mmol), DIPEA (0.233 ml, 1.337 mmol), HOBt hydrate (0.102 g,0.668 mmol) and EDCI (0.128 g, 0.668 mmol) as described in the previousExample affording 0.115 g of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 1.19 (d, 3H), 2.41 (s, 3H), 4.32 (m, 2H), 4.43 (m, 1H), 6.95(d, 1H), 7.33 (d, 1H) 7.37 (d, 1H), 7.79 (d, 1H), 7.85 (d, 1H), 7.94 (m,2H), 8.07 (d, 1H), 8.45 (m, 2H), 8.55 (s, 1H).

Example 276(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(pyridin-3-yl)-1H-pyrazole-3-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.058 g,0.307 mmol), 1-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (0.080 g,0.307 mmol), DIPEA (0.160 ml, 0.921 mmol), HOBt hydrate (0.071 g, 0.460mmol) and EDCI (0.088 g, 0.460 mmol) using the method of Example 274affording 0.120 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ1.18 (d, 3H), 4.38 (m, 2H), 4.50 (m, 1H), 6.89 (d, 1H), 6.95 (d, 1H),7.59 (m, 1H), 7.90 (m, 3H), 8.04 (d, 1H), 8.30 (m, 1H), 8.38 (d, 1H),8.60 (d, 1H), 8.65 (d, 1H), 9.19 (d, 1H).

Example 277(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.063 g,0.384 mmol), 3H-imidazo[4,5-b]pyridine-5-carboxylic acid (0.100 g, 0.384mmol), DIPEA (0.200 ml, 1.151 mmol), HOBt hydrate (0.088 g, 0.575 mmol)and EDCI (0.110 g, 0.575 mmol) using the method of Example 274 affording0.130 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ 1.17 (d,3H), 4.45 (m, 3H), 6.93 (d, 1H), 7.99 (m, 6H), 8.64 (s, 1H), 8.99 (d,1H).

Example 278(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(pyridin-4-yl)-1H-pyrazole-3-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.058 g,0.307 mmol), 1-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid (0.080 g,0.307 mmol), DIPEA (0.160 ml, 0.921 mmol), HOBt hydrate (0.071 g, 0.460mmol) and EDCI (0.088 g, 0.460 mmol) using the method of Example 274affording 0.110 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO): δ1.19 (d, 3H), 4.36 (m, 2H), 4.49 (m, 1H), 6.90 (d, 1H), 6.94 (d, 1H),7.85 (d, 1H), 7.90 (m, 2H), 7.94 (m, 2H), 8.02 (s, 1H), 8.38 (d, 1H),8.69 (m, 2H), 8.75 (d, 1H).

Example 279(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.060 g, 0.215 mmol), 3H-imidazo[4,5b]pyridine-5-carboxylic acid (0.035g, 0.215 mmol), DIPEA (0.112 ml, 0.646 mmol), HOBt hydrate (0.050 g,0.323 mmol) and EDCI (0.062 g, 0.323 mmol) using the method of Example274 affording 0.050 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO):δ 1.22 (d, 3H), 4.46 (m, 3H), 6.99 (d, 1H), 7.81 (d, 1H), 7.89 (m, 3H),8.09 (d, 1H), 8.63 (s, 1H), 8.80 (d, 1H), 13.00 (bs, 1H).

Example 280(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.060 g, 0.215 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.044g, 0.215 mmol), DIPEA (0.112 ml, 0.646 mmol), HOBt hydrate (0.050 g,0.323 mmol) and EDCI (0.062 g, 0.323 mmol) using the method of Example274 affording 0.080 g of the title compound. ¹H-NMR (400 MHz; d6-DMSO):δ 1.20 (d, 3H), 4.40 (m, 2H), 4.51 (m, 1H), 7.02 (d, 1H), 7.81 (d, 1H),7.94 (m, 3H), 8.33 (s, 1H), 8.38 (d, 1H), 8.54 (d, 1H), 8.71 (d, 1H),9.25 (bs, 1H).

Example 281(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(pyridin-3-yl)-1H-pyrazole-3-carboxamide

The title compound was prepared from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.050 g, 0.179 mmol), 1-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid(0.034 g, 0.179 mmol), DIPEA (0.094 ml, 0.538 mmol l), HOBt hydrate(0.041 g, 0.269 mmol) and EDCI (0.052 g, 0.269 mmol) using the method ofExample 274 affording 0.079 g of the title compound. ¹H-NMR (400 MHz;d6-DMSO): δ 1.19 (d, 3H), 4.38 (m, 2H), 4.49 (m, 1H), 6.89 (d, 1H), 7.01(d, 1H), 7.59 (m, 1H), 7.88 (m, 3H), 8.30 (m, 1H), 8.35 (d, 1H), 8.59(d, 1H), 8.65 (d, 1H), 9.18 (d, 1H).

Example 2823-Acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)isoxazol-5-yl)ethyl)-1H-pyrazole-5-carboxamidea) (E)-2-Chloro-4-((hydroxyimino) benzonitrile

2-chloro-4-formylbenzonitrile (2.0 g, 12.08 mmol) was dissolved in dryTHF (30 ml). Pyridine (2.9 ml, 36.2 mmol) and hydroxylaminehydrochloride (1.68 g, 24.16 mmol) was added to the solution. Themixture was heated to 70° C. and stirred for 4 h. THF was evaporated andice water (50 ml) was added. The mixture was stirred for 1 h and theprecipitate was filtered off and washed twice with cold water. Afterdrying at 35° C. overnight (2.04 g) of the title compound was obtained.¹H-NMR (400 MHz; d6-DMSO): 7.75 (dd, 1H), 7.90 (d, 1H), 7.99 (d, 1H),8.23 (s, 1H), 11.93 (s, 1H).

b) (Z)-3-Chloro-4-cyano-N-hydroxybenzimidoyl Chloride

(E)-2-chloro-4-((hydroxyimino) benzonitrile (2.04 g, 11.30 mmol) wasdissolved in DMF (20 ml) and cooled to 0° C. N-Chlorosuccinimide (1.66g, 12.43 mmol) was added and the mixture was allowed to warm to RT. Thereaction mixture was stirred for 2 h at RT and poured into ice water.The product was filtered and dried to give 2.26 g of the title compound.¹H-NMR (400 MHz; d6-DMSO): δ 7.92 (dd, 1H), 8.03 (d, 1H), 8.08 (d, 1H),13.06 (s, 1H).

c) tert-Butyl(2-(3-(3-chloro-4-cyanophenyl)isoxazol-5-yl)ethyl)carbamate

tert-Butyl but-3-yn-1-ylcarbamate (0.7 g, 4.14 mmol) was dissolved intoluene (20 ml) and triethylamine (0.87 ml) was added at RT.(Z)-3-chloro-4-cyano-N-hydroxybenzimidoyl chloride (0.98 g, 4.55 mmol)was added in DMF (2 ml) to reaction mixture. After one hour in RT thereaction mixture was heated to 40° C. for 2 h. The white precipitate wasfiltered and the filtrate was washed with 1 M HCl, water and brine.Dried over anhydrous Na₂SO₄, filtered and evaporated. The crude productwas purified by Flash chromatography (Heptane-EtOAc 2:1). Productfractions were combined and evaporated to give pure title compound (0.78g). ¹H-NMR (400 MHz; d6-DMSO): δ 1.35 (s, 9H), 2.95 (t, 2H), 3.30 (m,2H), 7.04 (m, 2H), 8.00 (d, 1H), 8.12 (d, 1H), 8.18 (s, 1H).

d) 4-(5-(2-Aminoethyl)isoxazol-3-yl)-2-chlorobenzonitrile Hydrochloride

tert-Butyl (2-(3-(3-chloro-4-cyanophenyl)isoxazol-5-yl)ethyl)carbamate(078 g, 2.24 mmol) was stirred with 13 w-% ethylacetate HCl solution (20ml) for 2 h at RT. The mixture was filtered and the precipitate waswashed with EtOAc, dried in vacuo at 30° C. overnight. The titlecompound 0.53 g was obtained. ¹H-NMR (400 MHz; d6-DMSO): δ 3.21 (m, 4H),7.22 (s, 1H), 8.02 (d, 1H), 8.14 (d, 1H), 8.20 (s, 1H), 8.27 (bs, 3H).

e)3-Acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)isoxazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide

The title compound was prepared from4-(5-(2-aminoethyl)isoxazol-3-yl)-2-chlorobenzonitrile hydrochloride(0.080 g, 0.282 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.043 g,0.282 mmol), DIPEA (0.196 ml, 1.126 mmol l), HOBt hydrate (0.065 g,0.422 mmol) and EDCI (0.081 g, 0.422 mmol) using the method of Example274 affording 0.013 g of the title compound after preparative HPLCpurification. ¹H-NMR (400 MHz; d6-DMSO): δ 2.53 (s, 3H), 3.20 (t, 2H),3.83 (m, 2H), 6.54 (s, 1H), 7.33 (bs, 1H), 7.63 (bs, 1H), 7.79 (m, 1H),7.97 (bs, 1H).

Example 283N-(2-(3-(3-chloro-4-cyanophenyl)isoxazol-5-yl)ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxamide

The title compound was prepared from4-(5-(2-aminoethyl)isoxazol-3-yl)-2-chlorobenzonitrile hydrochloride(0.080 g, 0.282 mmol), 5-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid(0.053 g, 0.282 mmol), DIPEA (0.196 ml, 1.126 mmol l), HOBt hydrate(0.065 g, 0.422 mmol) and EDCI (0.081 g, 0.422 mmol) using the method ofExample 274. The title compound was converted to HCl salt by treatmentof 1 M HCl ether solution for 2 h affording 0.056 g of the titlecompound. ¹H-NMR (400 MHz; d6-DMSO): 3.15 (t, 2H), 3.66 (m, 2H), 7.16(s, 1H), 7.42 (bs, 1H), 7.90 (m, 1H), 8.02 (d, 1H), 8.13 (d, 1H), 8.21(s, 1H), 8.63 (d, 1H), 8.75 (d, 1H), 8.83 (bs, 1H), 9.19 (s, 1H).

Example 284 Pyridine-2-carboxylic Acid{(E)-2-[5-(3,4-dichlorophenyl)furan-2-yl]vinyl}amide a)2-Bromo-5-((E)-2-nitrovinyl)furan

5-Bromo-2-furaldehyde (5.26 g, 0.0300 mol) and nitromethane (2.2 ml,2.43 g, 0.0300 mol) in methanol (40 ml) were added to NaOH (1.20 g,0.0300 mol) in water (40 ml) at 0° C. The resulting mixture was stirredat 0° C. for 2 h and then diluted with ice-cold water (25 ml). Theresulting solution was added slowly to 10% HCl (10 ml) at <0° C. Theseparated precipitate was filtered off, washed with water and heptaneand dried to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆): 6.90(1H, d), 7.30 (1H, d), 7.77 (1H, d), 7.96 (1H, d)

b) 2-Bromo-5-(2-nitro-1-phenylsulfanylethyl)furan

2-Bromo-5-((E)-2-nitrovinyl)furan (1.50 g, 0.006880 mol), thiofenol(0.91 ml, 0.99 g, 0.008945 mol) and N-isopropylcyclohexylamine (0.1 ml,0.085 g, 0.0006017 mol) in dry methylene chloride (150 ml) was stirredin nitrogen atmosphere at RT for 4.5 h. Then the solution was washedwith water, dried with Na₂SO₄ and evaporated. The product was stored ina freezer. ¹H NMR (400 MHz, DMSO-d₆): 4.94-5.01 (1H, m), 5.11-5.17 (2H,m), 6.37 (1H, d), 6.49 (1H, d), 7.38 (5H, m).

c) 2-(5-Bromofuran-2-yl)-2-phenylsulfanylethylamine

Zinc powder (0.80 g, 0.01224 mol) was added to2-bromo-5-(2-nitro-1-phenyl-sulfanylethyl)furan (0.60 g, 0.001828 mol)dissolved in the mixture of glacial acetic acid (24 ml) and concentratedhydrochloric acid (2.4 ml) at 80° C. in nitrogen atmosphere. The mixturewas heated at 80° C. for 2.5 h. Then, 0.40 g (0.00612 mol) of zincpowder was added and the mixture was heated for 1 h. The reactionmixture was cooled and 36 ml of water was added. pH was adjusted to 9 by2.5 M NaOH. The product was extracted into ethyl acetate. The organicphase was washed with water, dried and evaporated. ¹H NMR (400 MHz,DMSO-d₆): 2.87 (1H, distorted dd), 2.97 (1H, distorted dd), 4.41 (1H,t), 6.21 (1H, d), 6.45 (1H, d), 7.31 (5H, m).

d) Pyridine-2-carboxylic Acid[2-(5-bromofuran-2-yl)-2-phenylsulfanylethyl]amide

2-(5-Bromofuran-2-yl)-2-phenylsulfanylethylamine (0.28 g, 0.0009389mol), 2-pyridinecarboxylic acid (0.12 g, 0.001005 mol) and EDCI werestirred in dry THF (10 ml). After disappearing of the starting materialthe solvent was evaporated. Then chloroform was added and the solutionwas washed with 1 M Na₂CO₃ and water, dried with Na₂SO₄ and evaporated.The crude product was purified by flash chromatography usingheptane-EtOAc as a gradient eluent (85:15-70:30). ¹H NMR (400 MHz,DMSO-d₆): 3.75-3.80 (2H, m), 4.78-4.84 (1H, m), 6.33-6.37 (2H, m), 6.44(1H, d), 7.26-7.40 (4H, m), 7.59-7.62 (1H, m), 7.97-8.04 (2H, m),8.62-8.64 (1H, m), 9.08 (1H, m).

e) Pyridine-2-carboxylic Acid[2-benzenesulfinyl-2-(5-bromofuran-2-yl)ethyl]-amide

Sodium periodate (57 mg, 0.2677 mmol) in a small amount of water wasadded to pyridine-2-carboxylic acid[2-(5-bromofuran-2-yl)-2-phenylsulfanylethyl]-amide (90 mg, 0.2231 mmol)in methanol (13 ml). After refluxing for 4 h another 57 mg (0.2677 mmol)of sodium periodate was added and refluxing was continued for 4.5 h.Water (30 ml) was added and the product was extracted into EtOAc. Theorganic phase was washed with water, dried with Na₂SO₄ and evaporated.The crude product was used as such in the next step.

f) Pyridine-2-carboxylic Acid [(E)-2-(5-bromofuran-2-yl)vinyl]amide

The mixture of pyridine-2-carboxylic acid[2-benzenesulfinyl-2-(5-bromofuran-2-yl)ethyl]amide (0.11 g, 0.2623 mmol) and Na₂CO₃ (0.03 g, 0.2623 mmol) in toluene was refluxed innitrogen atmosphere for 2 h. The toluene solution was washed with 1 MNaOH (25 ml), dried with Na₂SO₄ and evaporated. The crude product waspurified by flash chromatography using heptane-EtOAc as a gradienteluent (90:10-80:20). The E isomer was used in the next step.

g) Pyridine-2-carboxylic Acid{(E)-2-[5-(3,4-dichlorophenyl)furan-2-yl]vinyl}-amide

Pyridine-2-carboxylic acid [(E)-2-(5-bromofuran-2-yl)vinyl]amide (0.014g, 0.0477 mmol) was dissolved in 1,4-dioxane (4.2 ml) in a microwavereaction vial. 3,4-Dichlorophenylboronic acid (0.0091 g, 0.0477 mmol),potassium phosphate tribasic (0.020 g, 0.0954 mmol), 0.7 ml of water andtetrakis(triphenylphosphine)-palladium(0) (0.005 g, 0.0047 mmol) wereadded. After removal of oxygen the reaction mixture was irradiated for10 min at 160° C. Then water (7 ml) was added. The product was extractedinto EtOAc (2×15 ml). The organic phase was washed with water, driedover Na₂SO₄ and evaporated. The crude product was purified by flashchromatography (eluent: heptane-EtOAc 7:3). ¹H NMR (400 MHz, CDCl₃):6.26 (1H, d), 6.29 (1H, d), 6.66 (1H, d), 7.45 (1H, distorted d),7.48-7.52 (2H, m), 7.69-7.76 (2H, m), 7.91 (1H, td), 8.27 (1H, d), 8.61(1H, dd), 9.88 (1H, d).

Example 285(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-isopropyl-1,2,4-oxadiazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.33 g,1.28 mmol), 3-isopropyl-1,2,4-oxadiazole-5-carboxylic acid (0.2 g, 1.28mmol), HOBt (0.26 g, 1.92 mmol), DIPEA (0.7 mL, 3.84 mmol) and EDCI(0.37 g, 1.92 mmol) using DMF (10 mL) as solvent. Yield 0.197 g. ¹H NMR(400 MHz; MeOD): δ 1.24 (d, 3H), 1.33 (d, 6H), 3.15 (m, 1H), 4.38 (m,2H), 4.57 (m, 1H), 6.78 (d, 1H), 7.71 (d, 1H), 7.77 (m, 1H), 7.87 (dd,1H), 8.02 (dd, 1H).

Example 286(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamidea)(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide

The title compound was prepared using the method of Example 34 (d)starting from 2-methyl-1H-imidazole-4-carboxylic acid (0.497 g, 3.94mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(1.2 g, 4.31 mmol) of Example 116(f). The product was purified byflash-chromatography. Yield 10.21%. 1H-NMR (400 MHz; DMSO-d6): δ 1.07(d, 3H), 2.31 (s, 3H), 4.25-4.46 (m, 3H), 7.02 (d, 1H), 7.42 (d, 1H),7.86 (d, 1H), 7.93 (dd, 1H), 8.00 (s, 1H), 8.07 (d, 1H), 12.11 (s, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide

1-Methylimidazole (1.030 μl, 0.013 mmol) and DMSO (3 ml) were added intoa flask.(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide(100 mg, 0.259 mmol) dissolved in 3 ml of DMSO was added. Lastly methylvinyl ketone (0.065 ml, 0.776 mmol) was added and the resulting mixturewas stirred in 70° C. for 2.5 h. The mixture was stirred at RT duringthe night and in the next morning the temperature was again raised to70° C. for 3.5 h. During the last part of the reaction a total of 0.195ml of methyl vinyl ketone and 16.48 μl of 1-methylimidazole were addedand the mixture was stirred at 70° C. for three days. 10 ml of water waspoured into the mixture and the resulting white solution was extractedwith ethyl acetate. Combined ethyl acetate phases were dried, filteredand evaporated. The product was purified by flash-chromatography andrecrystallization from ACN/water, respectively. Yield 42.3%. 1H-NMR (400MHz; DMSO-d6): δ 1.05 (d, 3H), 2.09 (s, 3H), 2.35 (s, 3H), 2.97 (t, 2H),4.04 (t, 2H), 4.23-4.45 (m, 3H), 7.01 (d, 1H), 7.48 (s, 1H), 7.85 (d,1H), 7.93 (dd, 1H), 8.00 (s, 1H), 8.05 (d, 1H).

Example 287(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(3-hydroxy-3-methylbutyl)-2-methyl-1H-imidazole-4-carboxamide

Methylmagnesium bromide 3M in Et₂O-solution (0.128 ml, 0.383 mmol) anddry THF (1 ml) were added into a flask and heated to 30° C.(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide(35 mg, 0.077 mmol) of Example 286(b) dissolved in THF (5 ml) was addedvery slowly. The reaction mixture was heated to 45° C. and stirred for 5h. Another batch of methylmagnesium bromide 3M in EtO₂-solution (0.128ml, 0.383 mmol) was added and the mixture was stirred at RT overnight.Next day the reaction mixture was poured into 10 ml of saturatedammonium chloride, THF was evaporated and the remaining water phase wasextracted with ethyl acetate. The ethyl acetate phases were combined,dried and evaporated. The product was purified by flash-chromatography.Yield 19.32%. 1H-NMR (400 MHz; DMSO-d6): δ 1.06 (d, 3H), 1.12 (s, 6H),1.69-1.77 (m, 2H), 2.34 (s, 3H), 3.92-3.98 (m, 2H), 4.25-4.46 (m, 4H),7.01 (d, 1H), 7.50 (s, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 8.00 (s, 1H),8.03 (d, 1H).

Example 288(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)imidazo[1,2-a]pyridine-2-carboxamidea) Imidazo[1,2-a]pyridine-2-carboxylic Acid

Into a flask containing a mixture of ethylimidazo[1,2-a]pyridine-2-carboxylate (1 g, 5.26 mmol), THF (5 ml) andwater (5 ml), lithium hydroxide (0.378 g, 15.77 mmol) was added andstirred overnight at RT. The pH of the reaction mixture was adjusted to2 with 2 M HCl and THF was evaporated. The remaining water phase wasextracted with ethyl acetate and the combined ethyl acetate phases weredried. The product had precipitated into the water phase. Water wasevaporated, and the remaining solid recrystallized from methanol. Theproduct was used as a salt in the next step. 1H-NMR (400 MHz; DMSO-d6):δ 7.23-7.26 (m, 1H), 7.63-7.70 (m, 1H), 7.76 (dd, 1H), 8.72 (s, 1H),8.73-8.77 (m, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide

The title compound was prepared using the method of Example 34(d)starting from imidazo[1,2-a]pyridine-2-carboxylic acid (0.853 g, 5.26mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(1.0 g, 3.59 mmol). The product was purified by flash chromatography andrecrystallization from acetonitrile/water, respectively. Yield 39.0%.1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 4.35 (dd, 1H), 4.43 (dd, 1H),4.47-4.57 (m, 1H), 6.96-7.01 (m, 1H), 7.02 (d, 1H), 7.34-7.40 (m, 1H),7.60 (dd, 1H), 7.89 (d, 1H), 7.93 (dd, 1H), 7.97 (s, 1H), 8.32 (d, 1H),8.55-8.58 (m, 1H), 8.61 (d, 1H).

Example 289(S)—N-(1-(3-(3-chloro-4-cyano-5-methoxyphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamidea)(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylic acid (0.096g, 0.560 mmol) of Example 77(a) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.12 g, 0.431 mmol) of Example 116(f). The product was purified byrecrystallization from ethanol. Yield 36.0%. 1H-NMR (400 MHz; DMSO-d6):δ 1.16 (d, 3H), 1.47 (s, 6H), 4.32 (d, 2H), 4.39-4.51 (m, 1H), 5.67 (s,1H), 6.49 (s, 1H), 7.01 (d, 1H), 7.85 (d, 1H), 7.87 (dd, 1H), 7.99 (s,1H), 8.74 (d, 1H).

b)(S)—N-(1-(3-(3-chloro-4-cyano-5-methoxyphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide

A mixture of(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide(50 mg, 0.116 mmol), 5 ml of dry methanol and cesium carbonate (75 mg,0.232 mmol) was reacted with stirring for 6 days keeping the temperatureat 60° C. during the day and at RT during the night. The mixture wasevaporated dissolved in DCM, extracted with water and dried. The productwas purified by flash chromatography. Yield 60.3%. 1H-NMR (400 MHz;DMSO-d6): δ 1.15 (d, 3H), 1.46 (s, 6H), 4.01 (s, 3H), 4.32 (d, 2H),4.40-4.51 (m, 1H), 5.68 (s, 1H), 6.49 (s, 1H), 7.00 (d, 1H), 7.54 (d,1H), 7.67 (d, 1H), 7.83 (d, 1H), 8.75 (d, 1H).

Example 290(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(pyridin-3-yl)-1H-imidazole-4-carboxamide

3-Pyridineboronic acid 1,3-propanediol ester (43.7 mg, 0.268 mmol),(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-imidazole-4-carboxamide(50 mg, 0.134 mmol), anhydrous copper(II) acetate (36.5 mg, 0.201 mmol),pyridine (0.022 ml, 0.268 mmol) and DCM (1 ml) were added into a flaskand stirred at RT for 47 h. The reaction mixture was extracted withethyl acetate, dried, filtered and evaporated. The product was purifiedby column chromatography. Yield 16.57%. 1H-NMR (400 MHz; CDCl₃): δ 1.24(d, 3H), 4.28 (dd, 1H), 4.47 (dd, 1H), 4.57-4.67 (m, 1H), 6.64 (d, 1H),7.48-7.55 (m, 2H), 7.74-7.78 (m, 1H), 7.81 (d, 1H), 7.88 (d, 1H),7.91-7.94 (m, 2H), 8.27 (d, 1H), 8.72 (d, 1H), 8.79 (d, 1H).

Example 291(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-benzo[d]imidazole-2-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 1H-benzo[d]imidazole-2-carboxylic acid (100 mg, 0.617mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(161 mg, 0.617 mmol) using N,N-dimethyl formamide as the solvent. Theproduct was purified by flash chromatography and recrystallized fromchloroform, respectively. Yield 20.03%. 1H-NMR (400 MHz; CDCl₃): δ 1.33(d, 3H), 4.32 (dd, 1H), 4.47 (dd, 1H), 4.64-4.75 (m, 1H), 6.59 (d, 1H),7.34-7.41 (m, 2H), 7.50 (d, 1H), 7.52-7.56 (m, 1H), 7.62 (d, 1H),7.81-7.87 (m, 2H), 8.00 (d, 1H), 8.42 (d, 1H), 10.87 (s, 1H).

Example 292(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3,3′-bipyridine-6-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 5-(pyridin-3-yl)picolinic acid (130 mg, 0.549 mmol) and(S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (150 mg,0.577 mmol) using N,N-dimethyl formamide as the solvent. The product waspurified by flash chromatography. Yield 45.2%. 1H-NMR (400 MHz;DMSO-d6): δ 1.18 (d, 3H), 4.38 (dd, 1H), 4.46 (dd, 1H), 4.49-4.59 (m,1H), 6.96 (d, 1H), 7.59 (q, 1H), 7.87 (d, 1H), 7.97 (dd, 1H), 8.01 (d,1H), 8.06-8.12 (m, 2H), 8.21-8.26 (m, 1H), 8.35 (dd, 1H), 8.69 (dd, 1H),9.01-9.07 (m, 2H), 9.14 (d, 1H).

Example 2931-(5-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)-1H-pyrazol-3-yl)ethylAcetate

A flask containingN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide(400 mg, 1.003 mmol) and DMAP (12.25 mg, 0.100 mmol) was put undernitrogen atmosphere. Pyridine (10 ml) was added, the reaction mixturecooled down to 0° C. and acetic anhydride (0.099 ml, 108 mg) was addeddropwise. The mixture was allowed to warm to RT and stirred overnight.Next day the mixture was evaporated and purified by flashchromatography. Yield 58.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.15 (d, 3H),1.51 (d, 3H), 2.02 (s, 3H), 4.25-4.37 (m, 2H), 4.39-4.49 (m, 1H), 5.88(q, 1H), 6.64 (s, 1H), 6.90 (dd, 1H), 7.80 (dd, 1H), 7.91-7.96 (m, 2H),8.04-8.07 (m, 1H), 8.15 (s, 1H), 13.24 (s, 1H).

Example 2941-(1-acetyl-3-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-pyrazol-5-yl)ethylAcetate

The title compound was isolated as a side product from the reactiondescribed in Example 293. Yield 1.920%. 1H-NMR (400 MHz; DMSO-d6): δ1.17 (d, 3H), 1.47 (dd, 3H), 2.04 (s, 3H), 2.72 (s, 3H), 4.29-4.41 (m,2H), 4.42-4.53 (m, 1H), 6.28 (q, 1H), 6.85 (d, 1H), 6.95 (d, 1H),7.83-7.85 (m, 1H), 7.9-7.94 (m, 1H), 7.97 (dd, 1H), 8.06 (s, 1H), 8.40(d, 1H).

Example 295(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 2-acetylthiazole-4-carboxylic acid (1.444 g, 8.44 mmol)and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (2.0g, 7.67 mmol). The product was purified by recrystallization fromethanol. Yield 93%. 1H-NMR (400 MHz; DMSO-d6): δ 1.20 (d, 3H), 2.70 (s,3H), 4.37 (dd, 1H), 4.44 (dd, 1H), 4.48-4.56 (m, 1H), 6.96 (d, 1H), 7.87(d, 1H), 7.92 (dd, 1H), 7.97 (dd, 1H), 8.04 (d, 1H), 8.48 (d, 1H), 8.61(s, 1H).

Example 2961-(4-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazol-2-yl)ethylacetate a)N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide

Into a flask containing(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide(1 g, 2.416 mmol) dissolved in ethanol (10 ml), sodium borohydride(0.137 g, 3.62 mmol) was added in small parts under nitrogen atmosphere.The following mixture was stirred overnight in RT. Next morning water (1ml) was added dropwise and the pH of the mixture was adjusted to under 7with 1 M HCl and the mixture was evaporated. 30 ml of ethyl acetate wasadded and stirred for 30 min, filtered and the filtrate was evaporatedand dried in vacuum at 40° C. The product was purified byrecrystallizing it twice from diethyl ether/ethanol to yield 41.6% ofthe title compound. 1H-NMR (400 MHz; DMSO-d6): δ 1.10-1.16 (m, 3H),1.44-1.48 (m, 3H), 4.29-4.52 (m, 3H), 4.94-4.02 (m, 3H), 6.22-6.26 (m,1H), 6.95-6.99 (m, 1H), 7.83-7.88 (m, 1H), 7.93-8.00 (m, 2H), 8.07-8.10(m, 1H), 8.11 (d, 1H), 8.33-4.39 (m, 1H).

b)1-(4-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazol-2-yl)ethylAcetate

N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxy-ethyl)thiazole-4-carboxamide(250 mg, 0.601 mmol), 4-dimethylaminopyridine (7.34 mg, 0.060 mmol) andpyridine (3 ml) were added into a flask and the mixture was cooled to 0°C. Acetic anhydride (0.063 ml, 0.661 mmol) was added dropwise and themixture was allowed to warm to RT with stirring. The reaction was leftto react overnight. Next morning more acetic anhydride (10 μl, 0.106mmol) was added and the reaction was stirred for another hour in RT. Themixture was evaporated and dried overnight in vacuum at 40° C. Theproduct was purified by recrystallization twice from ethanol/heptanes toyield 24.09% of final product. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d,3H), 1.62 (dd, 3H), 2.11 (s, 3H), 4.29-4.53 (m, 3H), 6.02-6.10 (m, 1H),6.94-6.98 (m, 1H), 7.84-7.87 (m, 1H), 7.92-8.00 (m, 2H), 8.07 (d, 1H),8.22 (d, 1H), 8.38-4.49 (m, 1H).

Example 297N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide

The following method allows preparation of pure diastereomers formoptically pure 1-hydroxyl propionamides. The procedure starting fromracemic starting material is described here.

a) 2-(tert-butyldiphenylsilyloxy)propanamide

2-hydroxy-propanamide (227 mg, 2.55 mmol), DMF (2 ml),tert-butylchloro-diphenyl-silane (1.0 ml, 1057 mg), imidazole (266 mg,3.91 mmol) and 4-dimethyl-amino-pyridine (93 mg, 0.764 mmol) dissolvedin DMF (2 ml) were stirred under nitrogen atmosphere over the weekend.After the weekend the temperature was raised to 90° C. and was left toreact for another 4 h. The mixture was then evaporated and extractedwith DCM/water and the combined organic phases were evaporated. Theproduct was purified by column chromatography. 1H-NMR (400 MHz;DMSO-d6): δ 1.04 (d, 9H), 1.12 (d, 3H), 4.00 (q, 1H), 7.04 (bs, 1H),7.24 (bs, 1H), 7.40-7.51 (m, 6H), 7.58-7.66 (m, 4H).

b) 2-(tert-butyldiphenylsilyloxy)propanethioamide

A flask containing2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (387mg, 0.957 mmol) was put under nitrogen atmosphere.2-(tert-butyl-diphenylsilyloxy)propanamide (622 mg, 1.899 mmol)dissolved in dry THF (10 ml) was added, temperature was raised to 60° C.and the mixture was allowed to react for 3 h. The solvent was evaporatedand the product was extracted from DCM/water. The product was used inthe next step without further purification. LC-MS: [M+1]=344.56.

c) 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-4-carboxylic Acid

A flask containing 3-bromopyruvic acid (317 mg, 1.901 mmol) was putunder nitrogen atmosphere.2-(tert-butyldiphenylsilyloxy)propanethioamide (653 mg, 1.901 mmol) wasdissolved in dry THF (8 ml) and added through a septum. The followingmixture was refluxed for two hours and then allowed to cool to RT. Thesolvent was evaporated and extracted with DCM/water and the combinedorganic phases were evaporated. 1H-NMR (400 MHz; DMSO-d6): δ 1.07 (s,9H), 1.35 (d, 3H), 5.14 (q, 1H), 7.39-7.54 (m, 2H), 7.57-7.61 (m, 2H),7.26-7.69 (m, 2H), 8.38 (s, 1H).

d)2-(1-(tert-butyldiphenylsilyloxy)ethyl)-N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide

The title compound was prepared using the method of Example 34(d)starting from2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-4-carboxylic acid (326mg, 0.792 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (105 mg,0.403 mmol). After extraction, based on the LC-MS data, the product wasestimated to be pure enough for the next step. LC-MS: [M+1]=655.30.

e)N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxyethyl)thiazole-4-carboxamide

2-(1-(tert-butyldiphenylsilyloxy)ethyl)-N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide(264 mg, 0.403 mmol) dissolved in THF (20 ml) and tetrabutylammoniumfluoride, 1.0 M solution in THF (0.41 ml, 0.410 mmol), were added into aflask and stirred at RT overnight. After reacting for an hour, more oftetrabutylammonium fluoride, 1.0 M solution in THF (0.41 ml, 0.410mmol), was added. The crude product was dried by evaporating andextracted with DCM/water. The organic phase was isolated with phaseseparator and evaporated. The product was purified by flashchromatography and recrystallization from ethyl acetate/heptane,respectively. 1H-NMR (400 MHz; DMSO-d6): δ 1.10-1.15 (m, 3H), 1.46 (t,3H), 4.29-4.52 (m, 3H), 4.93-5.01 (m, 1H), 6.24 (s, 1H), 6.94-6.98 (m,1H), 7.83-7.87 (m, 1H), 7.92-8.00 (m, 2H), 8.08 (s, 1H), 8.10 (d, 1H),8.33-8.39 (m, 1H).

Example 298(S)-3-acetyl-N-(1-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamidea) 5-(3,4-dichlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester(6.16 g, 22.13 mmol) and 4-Bromo-1,2-dichloro-benzene (2.84 ml, 22.13mmol) were dissolved in DMF (20 ml) under nitrogen atmosphere.Bis(triphenylphosphine)-palladium(II) chloride (0.777 g, 1.107 mmol) wasadded along with sodium carbonate (22.13 ml, 44.3 mmol) and theresulting mixture was stirred at 50° C. for 3 h. DMF was evaporated,water was added (15 ml) and extracted with ethyl acetate. Combinedorganic phases were dried with Na₂SO₄, filtered and dried with vacuum at40° C. The product was purified by recrystallization from diethyl etherand diethyl ether/heptane, respectively. 1H-NMR (400 MHz; DMSO-d6): δ1.50-1.69 (m, 3H), 1.77-1.84 (m, 1H), 1.91-2.00 (m, 1H), 2.31-2.44 (m,1H), 3.54-3.62 (m, 1H), 3.96-4.02 (m, 1H), 5.23 (dd, 1H), 6.89 (d, 1H),7.53 (dd, 1H), 7.60 (d, 1H), 7.77-7.82 (m, 2H).

b) 5-(3,4-dichlorophenyl)-1H-pyrazole

5-(3,4-Dichlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.840g, 9.56 mmol) and 10% HCl in EtOH (1.9 mmol/ml) (10 ml) were added intoa flask and stirred over the weekend at RT. The mixture was thenevaporated. Water (45 ml) was added and the mixture was neutralized withsaturated NaHCO₃. The mixture was extracted with ethyl acetate and thecombined organic phases dried with Na₂SO₄. The drying agent was filteredoff and the resulting mixture evaporated and dried with vacuum at 40° C.The product was used as such, without any further purifications. 1H-NMR(400 MHz; DMSO-d6): δ 6.83-6.86 (m, 1H), 7.65 (d, 1H), 7.72-7.86 (m,2H), 8.05 (d, 1H), 13.06 (s, 1H).

c) (S)-1-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)propan-2-amine

Into a flask containing 5-(3,4-dichlorophenyl)-1H-pyrazole (1.5 g, 7.04mmol), (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.357 g, 7.74 mmol)and triphenylphosphine (2.77 g, 10.56 mmol), dry THF (30 ml) was addedunder nitrogen atmosphere. After few minutes of stirring, DIAD (2.77 ml,14.08 mmol) was added dropwise through a septum while using icebath toprevent the temperature from rising. The resulting mixture was stirredat RT overnight. The mixture was evaporated. The Boc-protection wasremoved by adding ethanol (7 ml), 10% HCl/EtOH (50 ml), concentrated HCl(5 ml) and stirring the mixture over the weekend. The mixture wasevaporated, extracted with DCM/water. The pH of the water phase wasadjusted to ˜12 using 2 M NaOH and extracting the phase again with DCM.The combined organic phases were dried with Na₂SO₄, filtered andevaporated. 1H-NMR (400 MHz; DMSO-d6): δ 1.00 (d, 3H), 4.70-4.87 (m,3H), 6.84 (d, 1H), 7.65 (d, 1H), 7.76-7.84 (m, 2H), 8.02 (d, 1H).

d)(S)-3-acetyl-N-(1-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 3-acetyl-1H-pyrazole-5-carboxylic acid (71.9 mg, 0.466mmol) and (S)-1-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)propan-2-amine(126 mg, 0.466 mmol). The product was purified by recrystallization fromacetonitrile. Yield 12.61%. 1H-NMR (400 MHz; DMSO-d6): δ 1.05-1.25 (m,3H), 4.18-4.53 (m, 3H), 6.79 (s, 1H), 7.31 (s, 1H), 7.57-7.85 (m, 3H),7.89-7.98 (m, 1H), 8.39-8.54 (m, 1H), 14.05&14.12 (2 broad s, 1H).

Example 299(S,E/Z)—N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-(hydroxyimino)ethyl)-1H-pyrazole-5-carboxamide

Into a flask containing(S)-3-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide(50.0 mg, 0.126 mmol) of Example 78 dissolved in ethanol (3 ml) and THF(1 ml), hydroxylamine HCl (10.47 mg, 0.151 mmol) and anhydrous sodiumacetate (12.36 mg, 0.151 mmol) were added. The following mixture wasstirred at RT for 5 h after which 5 drops of dimethylamine was added.Stirring continued overnight. Next day the mixture was evaporated andextracted with ethyl acetate/water. The combined organic phases weredried with Na₂SO₄, filtered and evaporated. The crude product was driedwith vacuum at 40° C. over the weekend. The product was pure enoughwithout further purification steps. The product was obtained as amixture of E/Z isomers of oxime. Yield 82%. 1H-NMR (400 MHz; DMSO-d6): δ1.13-1.19 (m, 3H), 2.11 (s, 2H, E/Z), 2.16 (s, 1H, E/Z), 4.26-4.37 (m,2H), 4.40-4.51 (m, 1H), 6.97 (d, 1H), 7.71 (s, 1H), 7.74 (s, 1H),7.82-7.84 (m, 1H), 8.26 (bs, 1H), 11.07 (bs, ˜0.5H), 11.27 (bs, ˜0.5H),13.48 (bs, 1H).

Example 300N—((S)-1-(4-chloro-3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

Into a 0° C. solution containing sodium tetrahydroborate (0.022 g, 0.580mmol) dissolved in ethanol (1 ml),(S)-3-acetyl-N-(1-(4-chloro-3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide(0.125 g, 0.290 mmol) of Example 224 dissolved in 2 ml of ethanol wasadded slowly. The mixture was stirred at 0° C. for a few minutes afterwhich the mixture was allowed to warm to RT and the stirring wascontinued for 4.5 h. A few drops of water was added slowly. The pH wasadjusted below 4 with 2 M HCl. The solvent was evaporated and theresidue extracted with DCM/water. Organic phase was isolated with phaseseparator and evaporated. The product was purified by recrystallizationfrom ethanol. Yield 51.0%. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d, 3H),1.38 (d, 3H), 4.23-4.37 (m, 2H), 4.40-4.50 (m, 1H), 4.75-4.83 (m, 1H),5.40 (d, 1H), 6.40 (s, 1H), 8.00 (dd, 1H), 8.04 (dd, 1H), 8.05-8.14 (m,3H), 13.03 (s, 1H).

Example 301(R,E/Z)—N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-3-(1-(hydroxyimino)ethyl)-1H-pyrazole-5-carboxamidea)(R)-3-acetyl-N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 3-acetyl-1H-pyrazole-5-carboxylic acid (0.229 g, 1.486mmol) and(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile(0.380 g, 1.449 mmol). The product was purified by flash chromatography.Yield 64.4%. 1H-NMR (400 MHz; CDCl₃): δ 1.62 (d, 3H), 2.55 (s, 3H),3.74-3.83 (m, 1H), 3.90-3.98 (m, 1H), 4.60-4.69 (m, 1H), 6.59 (d, 1H),7.31 (bs, 1H), 7.51 (d, 1H), 7.53 (s, 1H), 7.55 (s, 1H), 7.60 (bs, 1H),10.97 (bs, 1H).

b)(R,E/Z)—N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-3-(1-(hydroxyimino)ethyl)-1H-pyrazole-5-carboxamide

Into a solution containing(R)-3-acetyl-N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide(50.2 mg, 0.126 mmol) dissolved in ethanol (3 ml), hydroxylaminehydrochloride (10.51 mg, 0.151 mmol) and anhydrous sodium acetate (12.40mg, 0.151 mmol) were added. After stirring the resulting at RT for 5 h,5 drops of dimethylamine was added and stirring was continued overnight.The mixture was evaporated, extracted with ethyl acetate/water, combinedorganic phases dried with Na₂SO₄, filtered and evaporated. The finalproduct was purified by flash chromatography. The product was obtainedas a mixture of E/Z isomers of oxime. Yield 81%. 1H-NMR (400 MHz;DMSO-d6): δ 1.48 (d, 3H), 2.10 (s, 2.25H, E/Z), 2.14 (s, 0.75H, E/Z),3.56-3.72 (m, 2H), 4.62-4.76 (m, 1H), 6.98 (d, 1H), 7.76 (s, 1H), 7.79(s, 1H), 7.90 (d, 1H), 8.19 (bs, ˜0.5H), 8.55 (bs, ˜0.5H), 10.98 (bs,˜0.5H), 11.31 (bs, ˜0.5H), 13.48 (s, 1H).

Example 302(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 5-(2-furyl)-2H-pyrazole-3-carboxylic acid (3.42 g, 19.18mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile(5 g, 19.18 mmol). The product was purified by flash chromatography andrecrystallization from acetonitrile, respectively. Yield 16.97%. 1H-NMR(400 MHz; CDCl₃): δ 1.26 (d, 3H), 4.30 (dd, 1H), 4.42 (dd, 1H),4.53-4.63 (m, 1H), 6.50 (dd, 1H), 6.62 (d, 1H), 6.67 (d, 1H), 6.94 (s,1H), 7.48 (dd, 1H), 7.53 (d, 1H), 7.68 (d, 1H), 7.73-7.84 (m, 2H), 8.02(s, 1H), 13.70 (broad s, 1H).

Example 303(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-4-cyano-1H-pyrazol-1-yl)propan-2-yl)-1-methyl-1H-imidazole-4-carboxamidea)4-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-chlorobenzonitrile

2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile(10 g, 34.8 mmol) and acetonitrile (120 ml) were added into a flask andthe temperature was adjusted to 0° C. with an ice bath.N-bromosuccinimide (6.80 g, 38.2 mmol) was added in small batcheskeeping the temperature below 5° C. The mixture was stirred at roomtemperature for 3 h. 10% NaHSO₃ (100 ml) was added and the mixture wasstirred for 15 min. The reaction mixture was extracted with DCM. Thecombined organic phases were dried, filtered and evaporated. The productwas purified by recrystallization from ethanol. Yield 82%. 1H-NMR (400MHz; DMSO-d6): δ 1.51-1.59 (m, 2H), 1.62-1.76 (m, 1H), 1.90-2.00 (m,2H), 2.06-2.18 (m, 1H), 3.62-3.70 (m, 1H), 3.91-3.98 (m, 1H), 5.49 (dd,1H), 8.02 (dd, 1H), 8.09 (d, 1H), 8.12 (d, 1H), 8.38 (s, 1H).

b)5-(3-chloro-4-cyanophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbonitrile

4-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-chlorobenzonitrile(3 g, 8.18 mmol), copper(I) cyanide (0.733 g, 8.18 mmol) andN,N-dimethyl formamide (15 ml) were loaded in a microwave reactor tube.The mixture was heated 190° C. for 5 h. The reaction was quenched bypouring the mixture into 200 ml of 12% ammonia solution and stirred for30 min. The precipitate was filtered, washed with water and dried invacuum at 40° C. The product was used in the next step without furtherpurification. LC-MS: [M+1]=313.75.

c) 5-(3-chloro-4-cyanophenyl)-1H-pyrazole-4-carbonitrile

To a solution containing5-(3-chloro-4-cyanophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbonitrile(2.686 g, 8.59 mmol) dissolved in ethanol (25 ml), 10% HCl solution inethanol (50 ml) was added and the resulting mixture was stirredovernight. The crude product was extracted with DCM/water. The pH of theaqueous phase was adjusted to 12 by adding 2 M NaOH. The aqueous phasewas again extracted with DCM. The combined organic phases were driedwith Na₂SO₄, filtered and evaporated. The product was purified by flashchromatography. 1H-NMR (400 MHz; DMSO-d6): δ 8.00-8.05 (m, 1H),8.13-8.19 (m, 2H), 8.75 (s, 1H), 14.24 (s, 1H).

d)(S)-1-(2-aminopropyl)-3-(3-chloro-4-cyanophenyl)-1H-pyrazole-4-carbonitrile

5-(3-chloro-4-cyanophenyl)-1H-pyrazole-4-carbonitrile (0.9 g, 3.94 mmol)dissolved in dry THF (15 ml), (S)-tert-butyl1-hydroxypropan-2-ylcarbamate (0.690 g, 3.94 mmol) and triphenylphosphine (1.549 g, 5.90 mmol) dissolved in dry THF (15 ml) were loadedinto a flask and cooled to 0° C. with an ice bath. Di-tert-butylazodicarboxylate (1.360 g, 5.90 mmol) was added slowly and stirred for10 min while keeping the temperature at 0° C. The temperature wasallowed to rise to RT and the mixture was stirred overnight. Next daythe mixture was evaporated and the intermediate deprotected by adding10% HCl/EtOH solution (40 ml) and stirring overnight at RT. The mixturewas again evaporated and the residue extracted with DCM/water. The pH ofaqueous phase was adjusted to 12 by adding 2 M NaOH and extracted againwith DCM. The organic phase was isolated with phase separator andevaporated. The product was used in the next step without furtherpurification. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d, 3H), 4.27-4.39 (m,3H), 6.50 (s, 2H), 8.02 (dd, 1H), 8.15-8.19 (m, 2H), 8.79 (s, 1H).

e)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-4-cyano-1H-pyrazol-1-yl)propan-2-yl)-1-methyl-1H-imidazole-4-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 1-methyl-1H-imidazole-4-carboxylic acid (53.0 mg, 0.420mmol) and(S)-1-(2-aminopropyl)-3-(3-chloro-4-cyanophenyl)-1H-pyrazole-4-carbonitrile(100 mg, 0.350 mmol). The product was purified by recrystallization fromdiethyl ether and diethyl ether/ethanol, respectively. Finally theproduct was also run through flash chromatography. Yield 34.1%. 1H-NMR(400 MHz; DMSO-d6): δ 1.15 (d, 3H), 3.67 (s, 3H), 4.36-4.51 (m, 3H),7.56 (d, 1H), 7.69 (d, 1H), 7.98 (dd, 1H), 8.04-8.10 (m, 2H), 8.15 (dd,1H), 8.69 (s, 1H).

Example 304(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylic acid (184 mg,1.076 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(250 mg, 0.897 mmol). The product was purified by flash chromatography.Yield 79%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 1.52 (s, 6H), 4.31(dd, 1H), 4.41 (dd, 1H), 4.44-4.52 (m, 1H), 5.64 (s, 1H), 7.02 (d, 1H),7.84-7.88 (m, 2H), 7.97-7.98 (m, 1H), 8.10 (d, 1H), 8.48 (s, 1H).

Example 305(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylic acid (197 mg,1.151 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (250 mg,0.959 mmol). The product was purified by flash chromatography. Yield57.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 1.53 (s, 6H), 4.31(dd, 1H), 4.40 (dd, 1H), 4.43-4.52 (m, 1H), 5.66 (s, 1H), 6.97 (d, 1H),7.84 (d, 1H), 7.94-8.00 (m, 2H), 8.08-8.10 (m, 1H), 8.17 (d, 1H), 8.48(s, 1H).

Example 3061-(5-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)-1H-pyrazol-3-yl)ethylPivalate

Into a solution containingN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide(53 mg, 0.133 mmol) dissolved in dry pyridine (2 ml),2,2-dimethylpropionic acid anhydride (0.031 ml, 0.153 mmol) was addeddropwise under nitrogen atmosphere. The resulting mixture was stirred atRT for 2 h after which DMAP (2.5 mg, 0.020 mmol) was added and thereaction mixture was left to react overnight. Next morning more2,2-dimethylpropionic acid anhydride (0.027 ml, 0.132 mmol) was addedand the mixture was again left to react overnight with stirring. Themixture was evaporated, extracted with DCM/water and the combinedorganic phases were evaporated. The product was purified by columnchromatography to obtain 51% yield. 1H-NMR (400 MHz; CDCl₃): δ 1.18 (d,9H), 1.21 (d, 3H), 1.65 (d, 3H), 4.25-4.32 (m, 1H), 4.38-4.46 (m, 1H),4.55-4.65 (m, 1H), 5.85-5.91 (m, 1H), 6.61 (t, 1H), 6.81-6.82 (m, 1H),7.51 (t, 1H), 7.64-7.68 (m, 1H), 7.73-7.77 (m, 1H), 7.99 (d, 1H), 8.17(dd, 1H).

Example 307N—((S)-1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide

(S)-5-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide(200 mg, 0.50 mmol) was dissolved in ethanol (10 ml) andsodiumborohydride (95 mg, 2.51 mmol) was added. The reaction mixture wasrefluxed for 2 h, cooled and saturated ammonium chloride (20 ml) wasadded. The mixture was extracted three times with ethyl acetate and thecombined organic fractions were washed with water, dried and evaporated.The residue was purified twice with reversed phase flash chromatographyto afford (6.7 mg, 3%) of the title compound. 1H-NMR (400 MHz; d6-DMSO):δ 1.13 (d, 3H), 1.37 (d, 3H), 4.24-4.40 (m, 2H), 4.39-4.53 (m, 1H),4.72-4.84 (m, 1H), 6.47 (s, 1H), 6.98 (m, 1H), 7.71-7.80 (m, 2H),7.79-7.88 (d, 1H), 8.15 (d, 1H).

Example 308(S)—N-(1-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methylisoxazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)-benzonitrile(120 mg, 0.408 mmol) and 5-methylisoxazole-3-carboxylic acid (62 mg,0.489 mmol). The product was purified with flash-chromatography. Yield88 mg (53%). 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.43 (s, 3H),4.32-4.34 (m, 2H), 4.40-4.50 (m, 1H), 6.43 (s, 1H), 7.02 (d, 1H), 7.84(d, 1H), 8.18 (d, 1H), 8.23-8.25 (m, 1H), 8.29 (s, 1H), 8.71 (d, 1H).

Example 309(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(methoxymethyl)-1H-pyrazole-5-carboxamidea) Ethyl 5-methoxy-2,4-dioxopentanoate

Under nitrogen atmosphere sodium (1.61 g, 70.0 mmol) was dissolved insmall pieces in a flask containing dry ethanol (150 ml). Diethyl oxalate(8.15 ml, 60 mmol) and methoxyacetone (5.52 ml, 60.0 mmol) were addedwith a syringe. The resulting mixture was stirred at RT for 1 h. Theflask was put in an ice bath and into it a mixture of sulphuric acid andice water was added dropwise. The resulting precipitate was filtered andwashed with DCM. The ethanol/DCM filtrate was evaporated. The residuewas dissolved in DCM, extracted with brine and the DCM phase dried withNa₂SO₄, filtered and evaporated. The product was purified with flashchromatography. 1H-NMR (400 MHz; DMSO-d6): δ 1.28 (t, 3H), 3.34 (s, 3H),4.19-4.23 (m, 2H), 4.27 (q, 2H).

b) Ethyl 3-(methoxymethyl)-1H-pyrazole-5-carboxylate

Ethyl 5-methoxy-2,4-dioxopentanoate (2.168 g, 11.52 mmol) was dissolvedin ethanol (100 ml) and hydrazine dihydrochloride (4.84 g, 46.1 mmol)was added. The resulting mixture was refluxed for 2 h. 200 ml of waterwas added and the pH of the mixture was neutralized with NaHCO₃. Themixture was extracted with ethyl acetate. The combined organic phaseswere washed with brine, dried with Na₂SO₄, filtered and evaporated. Theproduct was used in the next step without further purification. 1H-NMR(400 MHz; DMSO-d6): δ 1.29 (t, 3H), 3.26 (s, 3H), 4.27 (q, 2H), 4.42 (s,2H), 6.72 (s, 1H), 13.62 (s, 1H).

c) 3-(Methoxymethyl)-1H-pyrazole-5-carboxylic Acid

Ethyl 3-(methoxymethyl)-1H-pyrazole-5-carboxylate (2.44 g, 13.25 mmol)dissolved in methanol (40 ml) and cesium carbonate (8.63 g, 26.5 mmol)dissolved in water (40 ml) were loaded into a flask and stirredovernight at RT under nitrogen atmosphere. Ethyl acetate (100 ml) andwater (100 ml) were added and the pH was adjusted to 3 with 10% citricacid. Phases were separated and the water phase was extracted with moreethyl acetate. The combined organic phases were dried with Na₂SO₄,filtered and evaporated. The product was purified with flashchromatography. Yield 36.5%. 1H-NMR (400 MHz; DMSO-d6): δ 3.25 (s, 3H),4.40 (s, 2H), 6.67 (s, 1H), 13.16 (bs, 2H).

d)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(methoxymethyl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 3-(methoxymethyl)-1H-pyrazole-5-carboxylic acid (0.119 g,0.759 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.165 g,0.633 mmol). The product was purified with flash-chromatography. Yield5.07%. 1H-NMR (400 MHz; CDCl₃): δ 1.22 (d, 3H), 3.42 (s, 3H), 4.27 (dd,1H), 4.43 (dd, 1H), 4.54-4.62 (m, 3H), 6.62 (d, 1H), 6.69 (s, 1H), 7.49(d, 1H), 7.67 (d, 1H), 7.75 (dd, 1H), 7.83 (m, 1H), 8.17 (d, 1H).

Example 310(S)-3-acetyl-N-(1-(3-(4-cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)-benzonitrile(110 mg, 0.374 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (58 mg,0.374 mmol). The product was purified twice with flash-chromatography.Yield 8 mg (4%). 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 2.48 (m,3H), 4.29-4.38 (m, 2H), 4.41-4.50 (m, 1H), 7.01 (d, 1H), 7.29 (s, 1H),7.84 (d, 1H), 8.15-7.19 (m, 1H), 8.24 (s, 1H), 8.44-8.50 (m, 2H), 14.13(m, 1H).

Example 311(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methylisoxazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (240 mg,0.921 mmol) and 5-methylisoxazole-3-carboxylic acid (140 mg, 1.105mmol). The product was purified with flash-chromatography. Yield 46 mg(13%). 1H-NMR (400 MHz; d6-DMSO): δ 1.15 (d, 3H), 4.28-4.35 (m, 2H),4.40-4.50 (m, 1H), 6.45 (d, 1H), 6.93 (d, 1H), 7.81 (d, 1H), 7.91-7.93(m, 1H), 7.98 (d, 1H), 8.07 (d, 1H), 8.71 (d, 1H).

Example 312N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropyl)isoxazole-3-carboxamidea) 2-(Pent-4-yn-2-yloxy)tetrahydro-2H-pyran

(+/−)-4-Pentyn-2-ol (5.58 ml, 59.4 mmol) and 3,4-dihydro-2H-pyran (8.08ml, 89 mmol) were dissolved in DCM (100 ml). 4-Toluenesulfonic acidpyridine salt (1.494 g, 5.94 mmol) was added and the resulting mixturewas stirred for 4 h at RT with CaCl₂-tube. The mixture was concentrated.50 ml of diethyl ether was added, extracted with brine and dried withMgSO, filtered and evaporated. The product was used in the subsequentsteps without further purifications. LC-MS: [M+1]=169.23.

b) Ethyl5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoxazole-3-carboxylate

Ethyl chlorooximidoacetate (1 g, 6.60 mmol) and2-(pent-4-yn-2-yloxy)tetrahydro-2H-pyran (3.33 g, 19.80 mmol) weredissolved in diethyl ether (20 ml) and the mixture was stirredvigorously. Triethylamine (0.920 ml, 6.60 mmol) diluted with diethylether was added dropwise. The reaction mixture was extracted with waterand the organic phase dried with MgSO₄, filtered and evaporated. Theproduct was used in the next step without further purifications. LC-MS:[M+1]=284.32.

c) 5-(2-((Tetrahydro-2H-pyran-2-yl)oxy)propyl)isoxazole-3-carboxylicAcid

Ethyl 5-(2-(tetrahydro-2H-pyran-2-yloxy)propyl)isoxazole-3-carboxylate(1.87 g, 6.60 mmol) was dissolved in THF (20 ml). Lithium hydroxidemonohydrate 1 M (6.60 ml) was added and the resulting mixture wasstirred for overnight at RT. Next day more lithium hydroxide monohydrate1 M (3.3 ml+13.20 ml) was added and the mixture was again stirredovernight. THF was evaporated, water was added and pH was adjusted to 4with citric acid solution. The mixture was extracted four times withethyl acetate and the combined organic phases dried and evaporated.LC-MS: [M+1]=256.27.

d)N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoxazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from5-(2-(tetrahydro-2H-pyran-2-yloxy)propyl)isoxazole-3-carboxylic acid(0.392 g, 1.534 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g,0.767 mmol). The product was purified by reverse phase flashchromatography. LC-MS: [M+1]=498.97.

e)N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropyl)isoxazole-3-carboxamide

N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-(tetrahydro-2H-pyran-2-yloxy)propyl)isoxazole-3-carboxamide(0.1 g, 0.201 mmol), ethanol (2 ml) and hydrogen chloride, 10% in EtOH(0.5 ml, 1.350 mmol) were mixed together and stirred over the weekend atRT. The mixture was evaporated, more ethanol was added and evaporatedagain. The product was pure enough without further purifications. Yield51.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.09 (dd, 3H), 1.15 (d, 3H),2.82-2.86 (m, 2H), 3.91-3.98 (m, 1H), 4.29-4.34 (m, 2H), 4.41-4.50 (m,1H), 6.48-6.50 (m, 1H), 6.94 (d, 1H), 7.82 (d, 1H), 7.92 (dd, 1H), 7.97(d, 1H), 8.08-8.10 (m, 1H), 8.73 (d, 1H).

Example 313(S)-5-((1H-imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide

(S)-5-(bromomethyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)isoxazole-3-carboxamide(0.328 g, 0.731 mmol) of Example 197(a) was dissolved in acetonitrile(10 ml) and imidazole (0.31 g, 4.55 mmol) dissolved in acetonitrile (3ml) was added. The mixture was stirred at RT overnight. The mixture wasevaporated, the residue dissolved in ethyl acetate and extracted withwater. The organic phase was dried, filtered and evaporated. The productwas purified by recrystallization from ethyl acetate. Yield 13.81%.1H-NMR (400 MHz; DMSO-d6): δ 1.15 (d, 3H), 4.28-4.32 (m, 2H), 4.40-4.48(m, 1H), 5.50 (s, 2H), 6.63 (s, 1H), 6.93 (d, 1H), 6.93-6.94 (m, 1H),7.22-7.23 (m, 1H), 7.75-7.77 (m, 1H), 7.80 (d, 1H), 7.90 (dd, 1H), 7.96(d, 1H), 8.07 (d, 1H), 8.80 (d, 1H).

Example 314(S)-3-acetyl-4-chloro-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-1H-pyrazole-5-carboxamidea) Methyl 3-acetyl-4-chloro-1H-pyrazole-5-carboxylate

Into a flask containing methyl 3-acetyl-1H-pyrazole-5-carboxylate (4.0g, 0.0238 mol) in acetic acid (60 ml), 5% sodium hypochlorite (284 ml,0.190 mol) was added dropwise at 10-12° C. The mixture was stirred at RTover three nights adding more 5% sodium hypochlorite (177 ml, 0.119 molin total) during the second and third day. Water was added to thereaction mixture and the product was extracted with ethyl acetate.Organic layer was dried with anhydrous Na₂SO₄ and concentrated. Thecrude product was recrystallized twice from n-hexane. Yield 23%. LC-MS:[M+1]=203.5.

b) 3-Acetyl-4-chloro-1H-pyrazole-5-carboxylic Acid

To a mixture containing methyl3-acetyl-4-chloro-1H-pyrazole-5-carboxylate (1.3 g, 0.0064 mol) in THF(30 ml), lithium hydroxide (1.35 g, 0.032 mol) in water (15 ml) wasadded dropwise at 5-10° C. The reaction mixture was stirred at RT for 18h. Cold water (15 ml) was added and the pH was adjusted to ˜4 with 1 Npotassium bisulfate. The product was extracted with ethyl acetate, theorganic layer dried with anhydrous Na₂SO₄ and concentrated. The crudeproduct was purified by recrystallization from diethyl ether/n-hexane.Yield 56%. 1H-NMR (400 MHz; DMSO-d6): δ 2.57 (s, 3H), 13.91 (bs, 1H),14.69 (s, 1H).

c)(S)-3-acetyl-4-chloro-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 3-acetyl-4-chloro-1H-pyrazole-5-carboxylic acid (0.527 g,2.79 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.56 g,2.148 mmol). The product was purified by reverse phase flashchromatography. Yield 30.8%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H),2.54 (s, 3H), 4.31 (dd, 1H), 4.37 (dd, 1H), 4.42-4.51 (m, 1H), 6.95 (d,1H), 7.84 (d, 1H), 7.94 (dd, 1H), 7.98 (d, 1H), 8.06 (d, 1H), 8.27 (bs,1H), 14.45 (s, 1H).

Example 315(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-oxopropyl)isoxazole-3-carboxamidea) Ethyl 5-(2-hydroxypropyl)isoxazole-3-carboxylate

Ethyl chlorooximidoacetate (4 g, 26.4 mmol) and 4-pentyn-2-ol (10.00 ml,107 mmol) were dissolved in diethyl ether (30 ml). A solution oftriethylamine (3.68 ml, 26.4 mmol) in diethylether (20 ml) was addeddropwise to the reaction mixture. After 1 h of stirring at RT thereaction mixture was washed with brine and water, dried with MgSO₄ andevaporated to dryness. The residue was purified with flashchromatography using a gradient of methanol in methylene chlorideaffording 2.51 g (48%) of the title compound. 1H-NMR (400 MHz; d6-DMSO):δ, 1.11 (d, 3H), 1.31 (t, 3H), 2.82-2.94 (m, 2H), 3.93-4.03 (m, 1H) 4.35(q, 2H), 4.89 (d, 1H), 6.67 (s, 1H).

b) Ethyl 5-(2-oxopropyl)isoxazole-3-carboxylate

Ethyl 5-(2-hydroxypropyl)isoxazole-3-carboxylate (1.5 g, 7.53 mmol) wasdissolved in acetone (40 ml) and cooled to 0° C. Jones' reagent (5.90ml, 7.91 mmol) was added dropwise and the reaction mixture was stirredat 0 C for 30 min. Then the reaction mixture was allowed to warm up toRT and stirred 18 h. Mixture of methanol (30 ml) and water (30 ml) wasadded and then the volatiles were evaporated. The residue was extractedwith DCM, dried with Na2SO4 and evaporated to dryness to afford 1.38 g(93%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ, 1.32 (t, 3H),2.22 (s, 3H), 4.29-4.44 (m, 2H), 4.22 (s, 2H), 6.67 (s, 1H).

c) 5-(2-Oxopropyl)isoxazole-3-carboxylic Acid

Ethyl 5-(2-oxopropyl)isoxazole-3-carboxylate (0.65 g, 3.30 mmol) wasdissolved in ethanol (10 ml). A solution of cesium carbonate (1.611 g,4.94 mmol) in water (5 ml) was added to the reaction mixture and it wasstirred for 7 h at RT. The reaction mixture was concentrated, dilutedwith water and pH was adjusted to 2 with citric acid. The aqueous phasewas extracted with ethyl acetate, dried with Na₂SO₄ and evaporated todryness afforded 0.203 g (36%) of the title compound. 1H-NMR (400 MHz;d6-DMSO): δ, 2.21 (s, 3H), 4.20 (s, 2H), 6.67 (s, 1H).

d)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-oxopropyl)isoxazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.767 mmol) and 5-(2-oxopropyl)isoxazole-3-carboxylic acid (169 mg,0.997 mmol). The product was purified with flash chromatography using agradient of methanol in DCM affording 101 mg (32%) of the titlecompound. 1H-NMR (400 MHz; CDCl₃): δ 1.23 (d, 3H), 1.54 (s, 3H), 3.96(s, 2H), 4.20-4.49 (m, 2H), 4.53-4.64 (m, 1H), 6.63 (d, 1H), 6.65-6.69(m, 1H), 7.48 (d, 1H), 7.69 (d, 1H), 7.79-7.90 (m, 2H), 8.04 (d, 1H).

Example 316(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.767 mmol) and 4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid (166mg, 0.997 mmol). The product was triturated with ethanol. Yield 111 mg(35%). 1H-NMR (400 MHz; d6-DMSO): δ 1.09 (d, 3H), 1.58-1.72 (m, 4H),2.54-2.61 (m, 4H), 4.24-4.46 (m, 3H), 6.94 (d, 1H), 7.82 (d, 1H), 7.99(s, 2H), 8.05-8.08 (m, 2H), 12.68 (s, 1H).

Example 317(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.767 mmol) and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylicacid (166 mg, 0.997 mmol). The product was triturated with acetonitrile.Yield 95 mg (46%). 1H-NMR (400 MHz; d6-DMSO): δ 1.09 (d, 3H), 4.09 (t,2H), 4.18 (t, 2H), 4.26-4.39 (m, 2H), 4.42-4.49 (m, 1H), 4.79 (s, 2H),6.38 (s, 1H), 6.95 (d, 1H), 7.82 (d, 1H), 7.97-7.99 (m, 2H), 8.09 (s,1H), 8.26 (d, 1H).

Example 3184-Chloro-N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide

Into a mixture containing sodium borohydride (0.044 g, 1.159 mmol) inethanol (10 ml),(S)-3-acetyl-4-chloro-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide(0.5 g, 1.159 mmol) of Example 314 was slowly added and the temperaturewas raised to 50° C. for 10 min. The reaction mixture was stirred at RTfor 19 h. Saturated ammonium chloride (30 ml) was added and the mixturewas extracted with ethyl acetate, combined organic layers dried withNa₂SO₄, filtered and evaporated. The product was purified with flashchromatography. Yield 45.6%. 1H-NMR (400 MHz; CDCl₃): δ 1.24 (d, 3H),1.58 (dd, 3H), 2.88 (bs, 1H), 4.25-4.32 (m, 1H), 4.41-4.49 (m, 1H),4.56-4.68 (m, 1H), 5.04-5.12 (m, 1H), 6.62 (d, 1H), 7.48-7.51 (m, 1H),7.61-7.67 (m, 2H), 7.70-7.75 (m, 1H), 8.01-8.07 (m, 1H), 11.27 (bs, 1H).

Example 319(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (90 mg,0.345 mmol) and 4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxylic acid(75 mg, 0.449 mmol). The product was purified with flash chromatography.Yield 111 mg (78%). 1H-NMR (400 MHz; CDCl₃): δ 1.24 (d, 3H), 1.69-1.83(m, 4H), 2.77-2.83 (m, 4H), 4.25-4.43 (m, 2H), 4.52-4.61 (m, 1H), 6.63(d, 1H), 7.37 (d, 1H), 7.49 (d, 1H), 7.70 (d, 1H), 7.86 (d, 1H), 7.94(d, 1H).

Example 320(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-6,7-dihydro-4H-pyrano[3,4-d]isoxazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 6,7-dihydro-4H-pyrano[3,4-d]isoxazole-3-carboxylic acid(0.101 g, 0.598 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.12 g,0.460 mmol). The product was purified by reverse phase flashchromatography. Yield 9.50%. 1H-NMR (400 MHz; CDCl₃): δ 1.25 (d, 3H),2.93 (t, 2H), 3.90 (t, 2H), 4.26 (dd, 1H), 4.42 (dd, 1H), 4.50-4.62 (m,1H), 4.86-4.90 (m, 2H), 6.64 (d, 1H), 7.50 (d, 1H), 7.64 (d, 1H), 7.71(d, 1H), 7.87 (dd, 1H), 7.95 (d, 1H).

Example 321(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(6-methylpyridin-2-yl)-1H-imidazole-4-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (220 mg,0.844 mmol) and 1-(6-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid(223 mg, 1.097 mmol). The product was triturated with acetonitrile.Yield 153 mg (40%). 1H-NMR (400 MHz; CDCl₃): δ 1.26 (d, 3H), 1.45 (s,3H), 2.59 (s, 1H), 4.28-4.45 (m, 2H), 4.55-4.64 (m, 1H), 6.62 (d, 1H),7.16 (d, 1H), 7.19 (d, 1H), 7.52 (d, 1H), 7.67 (d, 1H), 7.75 (t, 1H),7.80 (m, 1H), 7.89 (d, 1H), 8.12 (d, 1H), 8.21 (d, 1H).

Example 322(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)imidazo[1,2-a]pyrimidine-2-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.767 mmol) and imidazo[1,2-a]pyrimidine-2-carboxylic acid (163 mg,0.997 mmol). The product was triturated with acetonitrile. Yield 168 mg(54%). 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 4.32-4.45 (m, 2H),4.49-4.56 (m, 1H), 6.92 (d, 1H), 7.13-7.16 (m, 1H), 7.84 (d, 1H), 7.95(d, 1H), 8.03-8.06 (m, 2H), 8.25 (s, 1H), 8.67-8.69 (m, 1H), 8.75 (d,1H), 8.97-8.99 (m, 1H).

Example 323(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-fluoroimidazo[1,2-a]pyridine-2-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.767 mmol) and 3-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid (180mg, 0.997 mmol). The product was triturated with acetonitrile. Yield 217mg (67%). 1H-NMR (400 MHz; d6-DMSO): δ 1.15 (d, 3H), 4.31-4.44 (m, 2H),4.47-4.55 (m, 1H), 6.95 (d, 1H), 7.06 (t, 1H), 7.37 (m, 1H), 7.55-7.58(m, 1H), 7.85 (d, 1H), 7.97 (d, 1H), 8.08 (t, 1H), 8.31 (1H, d), 8.55(d, 1H).

Example 324(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)imidazo[1,2-a]pyrimidine-2-carboxamide

The title compound was prepared using the method of Example 34(d)starting from Imidazo[1,2-a]pyrimidine-2-carboxylic acid (0.076 g, 0.466mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.1 g, 0.359 mmol). The product was purified by recrystallization fromacetonitrile. Yield 46.0%. 1H-NMR (400 MHz; CDCl₃): δ 1.32 (d, 3H), 4.33(dd, 1H), 4.44 (dd, 1H), 4.57-4.67 (m, 1H), 6.57 (dd, 1H), 6.97 (dd,1H), 7.50 (d, 1H), 7.59 (dd, 1H), 7.71 (dd, 1H), 7.80 (d, 1H), 8.08 (s,1H), 8.47 (dd, 1H), 8.66 (dd, 1H).

Example 325(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-fluoroimidazo[1,2-a]pyridine-2-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.1 g, 0.359 mmol) and 3-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid(0.084 g, 0.466 mmol). The product was purified by recrystallizationfrom acetonitrile. Yield 37.9%. 1H-NMR (400 MHz; CDCl₃): δ 1.25 (d, 3H),4.30 (dd, 1H), 4.46 (dd, 1H), 4.59-3.69 (m, 1H), 6.62 (d, 1H), 6.91-6.96(m, 1H), 7.24-7.29 (m, 1H), 7.52-7.56 (m, 2H), 7.76-7.80 (m, 2H),7.94-7.97 (m, 1H), 8.08 (d, 1H).

Example 326(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid (0.078 g,0.466 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.1 g, 0.359 mmol). The product was purified by flash chromatography.Yield 65.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11 (d, 3H), 1.55-1.71 (m,4H), 2.53-2.60 (m, 4H), 4.27 (dd, 1H), 4.35 (dd, 1H), 4.38-3.46 (m, 1H),7.00 (d, 1H), 7.83-7.87 (m, 2H), 7.90-7.97 (m, 2H), 12.66 (s, 1H).

Example 327(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylicacid (0.078 g, 0.466 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.1 g, 0.359 mmol). The product was purified by recrystallization fromacetonitrile and by flash-chromatography, respectively. Yield 53.3%.1H-NMR (400 MHz; CDCl₃): δ 1.19 (d, 3H), 2.26-2.34 (m, 2H), 4.18-4.34(m, 5H), 4.41 (dd, 1H), 4.52-4.62 (m, 1H), 6.01 (s, 1H), 6.62 (d, 1H),7.50 (d, 1H), 7.66 (d, 1H), 7.70-7.75 (m, 2H).

Example 328(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylic acid(0.078 g, 0.466 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.1 g, 0.359 mmol). The product was purified by recrystallization fromacetonitrile. Yield 32.5%. 1H-NMR (400 MHz; CDCl₃): δ 1.22 (d, 3H), 2.79(t, 2H), 3.89-3.94 (m, 2H), 4.27 (dd, 1H), 4.39 (dd, 1H), 4.48-4.58 (m,1H), 4.84-4.94 (m, 2H), 6.61 (d, 1H), 7.52 (d, 1H), 7.65 (dd, 1H), 7.69(d, 1H), 7.80-7.82 (m, 1H).

Example 329(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4-hydroxypicolinamide

The title compound was prepared using the method of Example 34(d)starting from 5-Hydroxy-2-pyridinecarboxylic acid (0.139 g, 0.997 mmol)and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2g, 0.767 mmol). The product was purified by recrystallization fromethanol/water. Yield 22.19%. 1H-NMR (400 MHz; DMSO-d6): δ 1.10 (d, 3H),4.29-4.49 (m, 3H), 6.95 (d, 1H), 7.23 (dd, 1H), 7.83 (d, 1H), 7.85 (d,1H), 7.98-8.00 (m, 2H), 8.11-8.13 (m, 1H), 8.17 (d, 1H), 8.82 (d, 1H).

Example 330(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(6-methylpyridin-2-yl)-1H-imidazole-4-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 1-(6-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid(0.190 g, 0.933 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.2 g, 0.718 mmol). The product was purified by recrystallization fromacetonitrile. Yield 55.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H),2.53 (s, 3H), 4.31-4.52 (m, 3H), 7.01 (d, 1H), 7.29 (d, 1H), 7.72 (d,1H), 7.87-7.96 (m, 3H), 8.02-8.04 (m, 1H), 8.35 (d, 1H), 8.40 (d, 1H),8.58 (d, 1H).

Example 331(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamidea) (S)-tert-butyl2-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate

The title compound was prepared using the method of Example 34(d)starting from7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylicacid (0.044 g, 0.165 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.033 g,0.127 mmol). The product was purified by flash chromatography. LC-MS:[M+1]=510.988.

b)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide,HCl

(S)-tert-butyl2-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate(0.029 g, 0.057 mmol) was dissolved in ethanol (2 ml) and hydrogenchloride (gas in EtOH) ˜10% (0.173 ml) was added. The resulting mixturewas stirred at RT for 6 days, adding more hydrogen chloride (gas inEtOH) ˜10% (0.173+0.173+2 ml) during the last few days of the reaction.The solvent was evaporated, ethanol (5 ml) was added and the solvent wasevaporated again. This was repeated one more time. The product waspurified by recrystallization from acetonitrile. LC-MS: [M+1]=447.332.

c)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide(23 mg, 0.056 mmol) was dissolved in methanol (2 ml). Triethylamine(0.078 ml, 0.561 mmol), formaldehyde, 37 w-% solution in water (0.067ml, 0.561 mmol) and sodium cyanoborohydride (35.3 mg, 0.561 mmol) wereadded in the solution. The resulting mixture was stirred at RTovernight. The reaction mixture was diluted with DCM, extracted withNaHCO₃ solution, combined organic phases were dried with Na₂SO₄,filtered and evaporated. The product was purified with LC/MS-trigger.Yield 33.6%. 1H-NMR (400 MHz; CDCl₃): δ 1.26 (d, 3H), 2.55 (s, 3H), 2.90(t, 2H), 3.70 (d, 2H), 4.08 (t, 2H), 4.32 (dd, 1H), 4.40 (dd, 1H),4.54-4.65 (m, 1H), 6.61 (d, 1H), 7.48 (s, 1H), 7.50 (d, 1H), 7.67 (d,1H), 7.71 (d, 1H), 7.81 (dd, 1H), 8.02 (d, 1H), 8.06 (s, 1H).

Example 332(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-6,7-dihydro-4H-pyrano[3,4-d]isoxazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 6,7-dihydro-4H-pyrano[3,4-d]isoxazole-3-carboxylic acid(0.174 g, 1.026 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(0.22 g, 0.789 mmol). The product was purified by LC/MS-trigger. Yield13.26%. 1H-NMR (400 MHz; CDCl₃): δ 1.23 (d, 3H), 2.93 (t, 2H), 3.91 (t,2H), 4.27 (dd, 1H), 4.42 (dd, 1H), 4.50-4.60 (m, 1H), 4.89 (d, 2H), 6.63(d, 1H), 7.37 (d, 1H), 7.50 (d, 1H), 7.59 (dd, 1H), 7.76-7.77 (m, 1H).

Example 333(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamidea) 1H-imidazole-4-carbonitrile

A mixture of 4-formylimidazole (5 g, 52.0 mmol), pyridine (30 ml) andhydroxylamine hydrochloride (4.07 g, 58.5 mmol) was stirred for 2 h atRT. In the next step the mixture was heated to 100° C. and aceticanhydride (9.29 ml, 99 mmol) was added dropwise. Finally the temperatureof the reaction mixture was slowly lowered to RT with stirring. The pHof the mixture was adjusted to 7.9 with 30% NaOH. The water phase wasextracted with ethyl acetate and the combined organic phases were washedwith brine and evaporated. Toluene was added twice and evaporated. Theremains were recrystallized from toluene, filtered and the crystals werewashed with diisopropyl ether. 1H-NMR (400 MHz; DMSO-d6): δ 7.91 (s,1H), 8.10 (s, 1H), 13.01 (s, 1H).

b) 1-trityl-1H-imidazole-4-carbonitrile

Into a mixture containing triphenylmethyl chloride (1.647 g, 5.91 mmol),1H-imidazole-4-carbonitrile (0.5 g, 5.37 mmol) and dry acetonitrile (17ml), triethylamine (1.295 ml, 9.29 mmol) was added dropwise and theresulting mixture stirred overnight at RT. Hexane (1.6 ml) and water (17ml) were poured into the mixture and the stirring was continued foranother 30 min. The precipitate was filtered and dried with vacuum.1H-NMR (400 MHz; CDCl₃): δ 7.06-7.12 (m, 6H), 7.35-7.40 (m, 10H), 7.49(d, 1H).

c) (Z)—N′-hydroxy-1-trityl-1H-imidazole-4-carboximidamide

A mixture containing 1-trityl-1H-imidazole-4-carbonitrile (1.6 g, 4.77mmol), ethanol (20 ml), triethylamine (1.995 ml, 14.31 mmol) andhydroxylamine hydrochloride (0.663 g, 9.54 mmol) was heated to 70° C.and stirred 4 h. The mixture was cooled with an ice bath, some water (10ml) was added and the precipitated product filtered and washed well withwater. The product was dried with vacuum at 40° C. 1H-NMR (400 MHz;DMSO-d6): δ 5.43-5.50 (m, 2H), 7.01 (d, 1H), 7.04-7.13 (m, 6H),7.36-7.46 (m, 10H), 9.10 (d, 1H).

d) Ethyl 3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylate

A mixture containing(Z)—N′-hydroxy-1-trityl-1H-imidazole-4-carboximidamide (1.08 g, 2.93mmol) and pyridine (20 ml) was cooled to 0° C. Ethyl oxalyl chloride(0.426 ml, 0.520 g) was added dropwise and the resulting mixture wasstirred for 10 min and then let warm to RT. The reaction mixture wasthen heated to 70° C. and stirred for 2.5 h. The content of the flaskwas then poured into 50 ml of ice-water-mixture and extracted withtert-butylmethyl ether. The organic phase was dried and evaporated. Theproduct was purified by flash chromatography. 1H-NMR (400 MHz; DMSO-d6):δ 1.33 (t, 3H), 4.41 (q, 2H), 7.14-7.19 (m, 6H), 7.39-7.48 (m, 9H), 7.53(d, 1H), 7.72 (d, 1H).

e) 3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylic Acid

Ethyl 3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylate (1.1g, 2.442 mmol) was dissolved in ethanol (60 ml) and the resultingsolution was cooled to 0° C. Cesium carbonate (6.36 g, 19.53 mmol) wasdissolved in water (25 ml) and added into the solution. The reactionmixture was refluxed for 1 h. Ethanol was evaporated, diluted withwater, filtered and washed with water. The solid was dried in vacuum at40° C. The product was purified by recrystallization from THF and ethylacetate, respectively. LC-MS: [M+1]=423.435.

f)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.211g, 0.499 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.1 g,0.384 mmol). The product was purified by flash chromatography. LC-MS:[M+1]=666.142.

g)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide

Into a flask containing(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide(0.148 g, 0.223 mmol) a solution of THF (9 ml), formic acid (1 ml, 0.223mmol) and water (0.1 ml) was added. The resulting mixture was stirred atRT. During the next 2 days 7 ml of formic acid was added. The solventswere evaporated, acetonitrile was added and evaporated, repeating thisprocedure twice. The product was purified with LC/MS-trigger. Yield42.4%. 1H-NMR (400 MHz; MeOD): δ 1.33 (d, 3H), 4.36 (dd, 1H), 4.45 (dd,1H), 4.55-4.66 (m, 1H), 6.77 (s, 1H), 7.68-7.75 (m, 2H), 7.78-7.92 (m,3H), 8.00 (s, 1H), 8.14 (s, 1H).

Example 334(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-ethoxy-4-methyl-1H-pyrazole-5-carboxamidea) ethyl 5-ethoxy-4-methyl-1H-pyrazole-3-carboxylate

A solution of diethyl oxalpropionate (9.15 ml, 49.5 mmol) and hydrazinedihydrochloride (6.23 g, 59.3 mmol) in ethanol (50 ml) was refluxed for1 h. The mixture was then cooled and water (150 ml) was added. Thesolution was neutralised with solid NaHCO₃ and extracted four times withEtOAc. The organic phase was washed with brine and water, dried withNa₂SO₄ and evaporated to dryness affording 7.81 g (80%) of the titlecompound. LC-MS: [M+1]=199.22.

b) 5-ethoxy-4-methyl-1H-pyrazole-3-carboxylic Acid

2 M solution of sodium hydroxide (98 ml, 197 mmol) was added to asolution of 5-ethoxy-4-methyl-1H-pyrazole-3-carboxylate (7.8 g, 39.4mmol) in ethanol (70 ml) and THF (30 ml). The reaction mixture wasrefluxed for 3 h and then the solvents were evaporated and water (200ml) was added to the residue. It was acidified to pH 1 with conc. HCland extracted three times with EtOAc. The precipitate formed in theextraction was filtered and washed with EtOAc and the filtrateevaporated to dryness affording 4.2 g (62%) of the title compound.LC-MS: [M+1]=171.17.

c)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-ethoxy-4-methyl-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 3-ethoxy-4-methyl-1H-pyrazole-5-carboxylic acid (0.117 g,0.690 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.15 g,0.575 mmol). The product was purified with reverse phaseflash-chromatography. Yield 4.21%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d,3H), 1.28 (t, 3H), 1.94 (s, 3H), 4.10-4.17 (m, 2H), 4.28-4.33 (m, 2H),4.37-4.46 (m, 1H), 6.96 (d, 1H), 7.72 (d, 1H), 7.85 (d, 1H), 7.92 (dd,1H), 7.98 (d, 1H), 8.07 (d, 1H), 12.08 (s, 1H).

Example 335(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxyethyl)isoxazole-3-carboxamidea) Ethyl5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoxazole-3-carboxylate

Ethyl chlorooximidoacetate (1 g, 6.60 mmol) and2-(but-3-ynyloxy)tetrahydro-2H-pyran (3.05 g, 19.80 mmol) were dissolvedin diethyl ether (20 ml). Triethylamine (0.668 g, 6.60 mmol) was dilutedwith diethyl ether (10 ml) and added dropwise into previous mixture.After addition the reaction mixture was extracted with water and theorganic layer was dried with Na₂SO₄, filtered and evaporated. LC-MS:[M+1]=172.17.

b) 5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoxazole-3-carboxylic Acid

Ethyl 5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)isoxazole-3-carboxylate(1.77 g, 6.57 mmol) was dissolved in THF (20 ml). 1M lithium hydroxidemonohydrate (6.57 ml) was added and the resulting mixture stirred at RTfor 2 h. During the same day more of 1M lithium hydroxide monohydrate(19.71 ml in total) was added and the reaction mixture was stirredovernight. THF was evaporated, water was added and the pH was adjustedto 4 with citric acid solution. The mixture was extracted four timeswith ethyl acetate. The combined organic layers were dried andevaporated. LC-MS: [M+1]=242.24.

c)N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoxazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)isoxazole-3-carboxylic acid(0.222 g, 0.921 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g,0.767 mmol). The product was purified with reverse phaseflash-chromatography. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H),1.34-1.51 (m, 4H), 1.52-1.69 (m, 2H), 3.06 (t, 2H), 3.37-3.45 (m, 1H),3.61-3.71 (m, 2H), 3.85-3.93 (m, 1H), 4.28-4.34 (m, 2H), 4.41-4.50 (m,1H), 4.57-4.61 (m, 1H), 6.51 (d, 1H), 6.93 (d, 1H), 7.81 (d, 1H), 7.92(dd, 1H), 7.97 (dd, 1H), 8.08 (dd, 1H), 8.74 (d, 1H).

d)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxyethyl)isoxazole-3-carboxamide

Into a solution containingN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)isoxazole-3-carboxamide(0.04 g, 0.083 mmol) and ethanol (4 ml), hydrogen chloride, 10% in EtOH(0.5 ml, 1.350 mmol) was added. The resulting mixture was stirred for 2h at RT. The mixture was evaporated, 2 ml of diethyl ether was added andstirred. The precipitated product was filtered and washed with coldheptane. The product was pure enough without further purifications.Yield 85%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H), 2.92 (t, 2H), 3.69(t, 2H), 4.29-4.34 (m, 2H), 4.41-4.50 (m, 1H), 6.51-6.53 (m, 1H), 6.94(d, 1H), 7.82 (d, 1H), 7.92 (dd, 1H), 7.97 (dd, 1H), 8.09 (d, 1H), 8.73(d, 1H).

Example 336(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg,0.767 mmol) and 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylicacid (168 mg, 0.997 mmol). The product was purified withflash-chromatography. Yield 251 mg (80%). 1H-NMR (400 MHz; CDCl₃): δ1.21 (d, 3H), 2.27-2.32 (m, 2H), 4.14-4.20 (m, 2H), 4.26-4.43 (m, 4H),4.51-4.60 (m, 1H), 6.01 (s, 1H), 6.62 (d, 1H), 7.49 (d, 1H), 7.51 (d,1H), 7.66 (d, 1H), 7.81-7.84 (m, 1H), 8.03 (d, 1H).

Example 337(S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile(120 mg, 0.431 mmol) and 5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylicacid (96 mg, 0.560 mmol). The product was triturated with ethanol. Yield67 mg (36%). 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 1.47 (s, 6H),4.31-4.33 (m, 2H), 4.40-4.49 (m, 1H), 6.49 (s, 1H), 7.01 (d, 1H), 7.84(d, 1H), 7.85-7.88 (m, 1H), 7.99 (s, 1H), 8.74 (d, 1H).

Example 338(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamidea) (Z)-ethyl 2-hydroxy-2-(4-oxo-2H-pyran-3(4H,5H,6H)-ylidene)acetate

Lithium bis(trimethylsilyl)amide 1M solution (30.0 ml, 30.0 mmol) anddiethyl ether (40 ml) were added into a flask under nitrogen atmosphereand cooled to −72° C. with dry ice/acetone-bath.Tetrahydro-4H-pyran-4-one (3 g, 30.0 mmol) was diluted with diethylether (10 ml) and added slowly to the previously cooled mixture. Theresulting mixture was stirred at −70° C. for one hour. Diethyl oxalate(4.07 ml, 30.0 mmol) diluted with diethyl ether (10 ml) was added andthe reaction mixture was allowed to warm to RT and stirred overnight.The formed yellow precipitate was filtered, washed with cold diethylether and dried with vacuum at 40° C. 1H-NMR (400 MHz; d6-DMSO): δ 1.16(d, 3H), 1.92 (t, 2H), 3.68 (t, 2H), 3.98 (q, 2H), 4.19 (s, 2H).

b) Ethyl 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylate

(Z)-ethyl 2-hydroxy-2-(4-oxo-2H-pyran-3(4H,5H,6H)-ylidene)acetate (2.5g, 12.49 mmol) was dissolved in methanol (10 ml). Hydrazinehydrochloride (2.57 g, 37.5 mmol) was added and the resulting mixturewas refluxed for one hour. The mixture was allowed to warm to RT and thesolvent was evaporated. The residue was dissolved in DCM and extractedtwice with water. The organic layer was dried with Na₂SO₄, filtered andevaporated. The product was purified with flash chromatography. 1H-NMR(400 MHz; d6-DMSO): δ 1.27 (d, 3H), 2.70 (t, 2H), 3.81 (t, 2H), 4.24 (q,2H), 4.69 (s, 2H), 13.40 (bs, 1H).

c) 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylic Acid

Ethyl 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylate (0.97 g,4.94 mmol) was dissolved in methanol (20 ml) and cooled to 0° C. with anice bath. Sodium hydroxide 2 M solution (4.94 ml, 9.89 mmol) was addedand the mixture was allowed to cool to RT with stirring. The mixture wasstirred for 26 h during which additional 7 ml of sodium hydroxide 2 Msolution was added. The solvent was evaporated and the pH adjusted to 2with 1 M HCl. The formed precipitate was filtered and washed with water.The white solid was dried with vacuum at 40° C. 1H-NMR (400 MHz;d6-DMSO): δ 2.69 (t, 2H), 3.81 (t, 2H), 4.68 (s, 2H), 13.09 (bs, 1H).

d)(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylic acid(0.168 g, 0.997 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g,0.767 mmol). The product was triturated twice with acetonitrile. Yield65.7%. 1H-NMR (400 MHz; d6-DMSO): δ 1.11 (d, 3H), 2.70 (t, 2H),3.72-3.80 (m, 2H), 4.23-4.46 (m, 3H), 4.56-4.68 (m, 2H), 6.94 (d, 1H),7.82 (d, 1H), 7.97-8.00 (m, 2H), 8.07-8.09 (m, 1H), 8.21 (d, 1H). 12.98(s, 1H).

Example 339(S)-3-(1-benzyl-1H-imidazol-4-yl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamidea) Lithium(Z)-4-(1-benzyl-1H-imidazol-4-yl)-1-ethoxy-1,4-dioxobut-2-en-2-olate

5-acetyl-1-benzylimidazole (5 g, 24.97 mmol) was dissolved in drydiethyl ether (100 ml). The mixture was cooled to −78° C. with dryice/acetone-bath. Lithium bis(trimethylsilyl)amide (27.5 ml, 27.5 mmol)was added dropwise and the mixture was stirred at −78° C. for 1 h.Diethyl oxalate (4.41 ml, 32.5 mmol) was added and the reaction mixturewas allowed to warm to RT. The following mixture was stirred overnightat RT. The precipitated product was filtered, washed with diethyl etherand dried. 1H-NMR (400 MHz; d6-DMSO): δ, 1.22 (t, 3H), 4.11 (q, 2H),5.62 (s, 2H), 6.18 (s, 1H), 7.16-7.31 (m, 5H), 7.49 (d, 1H), 7.89 (d,1H).

b) Ethyl 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate

Into a suspension containing lithium(Z)-4-(1-benzyl-1H-imidazol-4-yl)-1-ethoxy-1,4-dioxobut-2-en-2-olate(3.0 g, 9.80 mmol) and ethanol (20 ml), hydrazine dihydrochloride (1.337g, 12.74 mmol) was added and the resulting mixture was refluxed for 3 hwith stirring. The mixture was allowed to cool to RT and the mixture wasevaporated. The residue was suspended in ethanol, stirred and filtered.The precipitate was washed with cold ethanol and dried with vacuum at40° C. 1H-NMR (400 MHz; d6-DMSO): δ, 1.31 (t, 3H), 4.33 (q, 2H), 5.82(s, 2H), 7.18-7.37 (m, 6H), 8.19 (s, 1H), 9.42 (s, 1H), 14.53 (bs, 1H).

c) 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic Acid

Ethyl 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (0.5 g,1.687 mmol) was dissolved in methanol (10 ml). The mixture was cooled to0° C. and sodium hydroxide 2 M solution (1.687 ml) was added. Thereaction mixture was allowed to warm to RT with stirring. Stirring wastwo days during which more sodium hydroxide 2 M solution (3.4 ml intotal) was added. The last hour was stirred at 40° C. Methanol wasevaporated and water was added. The pH was adjusted to 1 with 1M HCl,which precipitated the product out of the solution. The mixture wasfiltered, precipitate washed with water and dried with vacuum at 40° C.1H-NMR (400 MHz; d6-DMSO): δ, 5.82 (s, 2H), 7.17-7.38 (m, 6H), 8.17 (d,1H), 9.39 (s, 1H), 14.35 (bs, 1H).

d)(S)-3-(1-benzyl-1H-imidazol-4-yl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide

The title compound was prepared using the method of Example 34(d)starting from 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylicacid (0.268 g, 0.997 mmol) and(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g,0.767 mmol). The product was purified with flash chromatography. Yield44.9%. 1H-NMR (400 MHz; CDCl₃): δ 1.23 (d, 3H), 4.27 (dd, 1H), 4.41 (dd,1H), 4.53-4.63 (m, 1H), 5.26 (s, 2H), 6.61 (d, 1H), 6.76 (s, 1H),7.00-7.05 (m, 2H), 7.28-7.36 (m, 5H), 7.49 (d, 1H), 7.58-7.63 (m, 2H),7.78 (dd, 1H), 8.03 (s, 1H), 11.75 (bs, 1H).

Example 340(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide(100 mg, 0.271 mmol) was suspended in acetonitrile (5 ml).1,1-Difluoro-2-iodoethane (0.053 ml, 116 mg) and cesium carbonate (124mg, 0.380 mmol) were added and the resulting mixture was stirredovernight at RT. Next day 2 ml of THF and 50 μl of1,1-difluoro-2-iodoethane was added and the stirring was continued forthree more nights. Another 0.2 ml of 1,1-difluoro-2-iodoethane was addedand the reaction mixture was stirred overnight. The reaction mixture wasevaporated. 3 ml of N,N-dimethyl formamide was added and the mixturefiltered. Filtrate was purified with LC/MS-trigger. Yield 27.4%. ¹H-NMR(400 MHz; CDCl₃): δ 1.22 (d, 3H), 2.44 (s, 3H), 4.19-4.33 (m, 3H), 4.39(dd, 1H), 4.51-4.62 (m, 1H), 5.82-6.13 (m, 1H), 6.61 (d, 1H), 7.49 (d,1H), 7.52 (s, 1H), 7.64-7.71 (m, 2H), 7.85 (dd, 1H), 8.00 (d, 1H).

Example 341(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(2-fluoroethyl)-2-methyl-1H-imidazole-4-carboxamide

(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide(100 mg, 0.271 mmol) suspended in acetonitrile (5 ml). Into the mixture,cesium carbonate (124 mg, 0.380 mmol) and 1-Iodo-2-fluoroethane (0.049ml, 0.596 mmol) were added and the resulting mixture was stirredovernight at RT. Water (2 ml) was added and the mixture was evaporated.The product was purified with LC/MS-trigger. ¹H-NMR (400 MHz; CDCl₃): δ1.23 (d, 3H), 2.42 (s, 3H), 4.12-4.23 (m, 2H), 4.30 (dd, 1H), 4.39 (dd,1H), 4.51-4.61 (m, 1H), 4.58-4.73 (m, 2H), 6.61 (d, 1H), 7.49 (d, 1H),7.51 (d, 1H), 7.62 (d, 1H), 7.77 (dd, 1H), 7.85 (dd, 1H), 8.00 (dd, 1H).

Example 342(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-hydroxypropan-2-yl)thiazole-4-carboxamide

(S)-ethyl4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate(0.28 g, 0.611 mmol) was dissolved in dry THF under nitrogen atmosphere.The solution was cooled to −78° C. with acetone-dry ice-bath.Methylmagnesium bromide, 3 M solution in Et2O (0.408 ml, 1.223 mmol),was added dropwise. The reaction mixture was stirred in RT overnight.Next day the mixture was again cooled to −78° C. and 1.019 ml ofmethylmagnesium bromide, 3 M solution in Et₂O, was added. The mixturewas stirred in RT overnight. Saturated ammonium chloride was added andthe mixture was diluted with water and DCM. The organic phase was washedwith brine and water. The product was purified by Flash-chromatography.Yield 19.08%. 1H-NMR (400 MHz; CDCl₃): δ 1.28 (d, 3H), 1.58 (s, 6H),2.54 (s, 3H), 2.63 (s, 1H), 4.34 (dd, 1H), 4.44 (dd, 1H), 4.60 (m, 1H),6.43 (d, 1H), 7.52 (m, 3H), 7.83 (d, 1H), 8.00 (s, 1H).

Abbreviations

THF=Tetrahydrofuran

TFA=Trifluoroacetic acid

TEAB=Tetraethyl ammonium bromide

DCM=Dichloromethane

DMF=Dimethylformamide

EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HOBt=1-hydroxybenzotriazole

DIAD=Diisopropyl azodicarboxylate

DIPEA=N, N-diisopropylethylamine

DMSO=Dimethyl sulfoxide

DMAP=4-Dimethylaminopyridine

TLC=Thin layer chromatography

IPA=Isopropyl alcohol

BOC=tert-Butyloxycarbonyl

RT=Room temperature

DCC=Dicyclohexylcarbodiimide

1-11. (canceled)
 12. A compound, which is

2-chloro-4-(1H-pyrazol-5-yl)benzonitrile or

(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile.
 13. Thecompound according to claim 12, which is2-chloro-4-(1H-pyrazol-5-yl)benzonitrile.
 14. The compound according toclaim 12, which is(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile.
 15. Apharmaceutical dosage form comprising: a compound of formula (VI):

wherein R₁ is halogen; R₂ is cyano; R₃ is hydrogen, halogen, or methyl;R₄ is hydrogen; R₅ is methyl; ring A is any one of the following groupsor tautomers thereof:

R₈ is hydrogen, C₁₋₇ alkyl, or hydroxy C₁₋₇ alkyl; and R₉ is hydrogen,halogen, or C₁₋₇ alkyl, or a pharmaceutically acceptable salt thereof;and a pharmaceutically acceptable excipient.
 16. The dosage formaccording to claim 15, wherein ring A is

or a tautomer thereof.
 17. The dosage form according to claim 16,wherein R₈ is hydroxy C₁₋₇ alkyl; and R₉ is hydrogen.
 18. The dosageform according to claim 17, wherein R₁ is chlorine; R₃ is hydrogen; andR₈ is 1-hydroxyethyl.
 19. The dosage form according to claim 18, whereinthe compound isN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide.20. The dosage form according to claim 18, wherein the compound isN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide.21. A compound of formula (VI):

wherein R₁ is halogen; R₂ is cyano; R₃ is hydrogen, halogen, or methyl;R₄ is hydrogen; R₅ is methyl; ring A is any one of the following groupsor tautomers thereof:

R₈ is hydrogen, C₁₋₇ alkyl, or hydroxy C₁₋₇ alkyl; and R₉ is hydrogen,halogen, or C₁₋₇ alkyl, or a pharmaceutically acceptable salt thereof;and a pharmaceutically acceptable excipient.
 22. The compound accordingto claim 21, wherein ring A is

or a tautomer thereof.
 23. The compound according to claim 22, whereinR₈ is hydroxy C₁₋₇ alkyl; and R₉ is hydrogen.
 24. The compound accordingto claim 23, wherein R₁ is chlorine; R₃ is hydrogen; and R₈ is1-hydroxyethyl.
 25. The compound according to claim 24, wherein thecompound isN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide.26. The compound according to claim 24, wherein the compound isN—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide.